Hysteria

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https://en.wikipedia.org/wiki/Hysteria

Hysteria colloquially means ungovernable emotional excess and can refer to a temporary state of mind or emotion; however, beginning in 1900 B.C., hysteria was considered a diagnosable physical illness in females and then in the 1500s shifted to a mental illness. Many influential psychiatrists such as Sigmund Freud and Jean-Martin Charcot dedicated research to hysteria patients. Currently, most doctors practicing Western medicine do not accept hysteria as a medical diagnosis. The blanket diagnosis of hysteria has been fragmented into myriad medical categories such as epilepsy, histrionic personality disorder, conversion disorders, dissociative disorders, or other medical conditions. Furthermore, social deviances, such as deciding not to wed, are no longer considered psychological disorders.

Hysteria

History

The word hysteria originates from the Greek word “uterus,” hystera. The oldest record of hysteria dates back to 1900 B.C. when Egyptians recorded behavioral abnormalities in adult women on medical papyrus. The Egyptians attributed the behavioral disturbances to a wandering uterus—thus later dubbing the condition hysteria. To treat hysteria Egyptian doctors prescribed various medications. For example, doctors put strong smelling substances on the patients’ vulvas to encourage the uterus to return to its proper position. Another tactic was to smell or swallow unsavory herbs to encourage the uterus to flee back to the lower part of the female’s stomach.

The ancient Greeks accepted the ancient Egyptians’ explanation for hysteria; however, they included in their definition of hysteria the inability to bear children or the failure to marry. Ancient Romans also attributed hysteria to an abnormality in the womb; however, discarded the traditional explanation of a wandering uterus. Instead, the ancient Romans credited hysteria to a disease of the womb or a disruption in reproduction (i.e. a miscarriage, menopause, etc.).

 Hysteria theories from the ancient Egyptians, ancient Greeks, and ancient Romans were the basis of the Western understanding of hysteria.

Between the fifth and thirteenth centuries, however, the increasing influence of Christianity in the Latin West altered medical and public understanding of hysteria. St. Augustine's writings suggested that human suffering resulted from sin, and thus, hysteria became perceived as satanic possession. With the shift in perception of hysteria came a shift in treatment options. Instead of admitting patients to a hospital, the church began treating patients through prayers, amulets, and exorcisms. Furthermore, during the medieval and Renaissance periods many patients of hysteria were prosecuted as witches and underwent interrogations, torture, and execution.

However, during the sixteenth and seventeenth centuries activists and scholars worked to change the perception of hysteria back to a medical condition. Particularly, French physician Charles Lepois insisted that hysteria was a malady of the brain. In addition, in 1697, English physician Thomas Sydenham theorized that hysteria was an emotional condition, instead of a physical condition. Many physicians followed Lepois and Sydenham's lead and hysteria became disassociated with the soul and the womb. During this time period science started to focalize hysteria in the central nervous system. As doctors developed a greater understanding of the human nervous system, the neurological model of hysteria was created, which further propelled the conception of hysteria as a mental disorder.

In 1859 Paul Briquet defined hysteria as a chronic syndrome manifesting in many unexplained symptoms throughout the body's organ systems. What Briquet described became known as Briquet's syndrome, or Somatization disorders, in 1971. Over a ten year period, Briquet conducted 430 case studies of patients with hysteria. Following Briquet, Jean-Martin Charcot studied women in an asylum in France and used hypnosis as treatment. He also mentored Pierre Janet, another French psychologist, who studied five of hysteria's symptoms (anesthesia, amnesia, abulia, motor control diseases, and character change) in depth and proposed that hysteria symptoms occurred due to a lapse in consciousness. Both Charcot and Janet inspired Sigmund Freud's work. Freud theorized hysteria stemmed from childhood sexual abuse or repression, and was also one of the first to apply hysteria to men.

During the 20th century, as psychiatry advanced in the West, anxiety and depression diagnoses began to replace hysteria diagnoses in Western countries. For example, from 1949 to 1978 annual admissions of hysteria patients in England and Wales decreased by roughly two thirds. With the decrease of hysteria patients in Western cultures came an increase in anxiety and depression patients. Although declining in the West, in Eastern countries such as Sudan, Egypt, and Lebanon hysteria diagnoses remained consistent.

Theories for why hysteria diagnoses began to decline vary, but many historians infer that World War II, westernization, and migration shifted Western mental health expectations. Twentieth century western societies expected depression and anxiety manifest itself more in post World War II generations and displaced individuals; and thus, individuals reported or were diagnosed accordingly . In addition, medical advancements explained aliments that were previously attributed to hysteria such as epilepsy or infertility . After a gradual decline in diagnoses and reports, in 1980 hysteria was removed from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), which had included hysteria as a mental disorder from its second publication in 1968.

Historical symptoms

Historically, the symptoms of hysteria have a large range.

Hysteria Patient

For example:

• Shortness of breath
• Anxiety
• Insomnia
• Fainting

• Amnesia
• Paralysis
• Pain
• Spasms
• Convulsive fits
• Vomiting
• Deafness
• Bizarre movements
• Seizures
• Hallucinations
• Inability to speak

Notable figures

Jean-Martin Charcot

In the late nineteenth century, French neurologist Jean-Martin Charcot, attempted to tackle what he referred to as, "the great neurosis" or hysteria. Charcot theorized that hysteria was a hereditary, physiological disorder. He believed hysteria impaired areas of the brain which provoked the physical symptoms displayed in each patient. While Charcot believed hysteria was hereditary, he also thought that environmental factors such as stress could trigger hysteria in an individual.

Charcot published over 120 case studies of patients who he diagnosed with hysteria, including Marie "Blanche" Whittman. Whittman was referred to as the "Queen of Hysterics," and remains the most famous patient of hysteria. To treat his patients, Charcot used hypnosis, which he determined was only successful when used on hysterics. Using patients as props, Charcot executed dramatic public demonstrations of hysterical patients and his cures for hysteria, which many suggest produced the hysterical phenomenon. Furthermore, Charcot noted similarities between demon possession and hysteria, and thus, he concluded "demonomania" was a form of hysteria.

Sigmund Freud

In 1896 Sigmund Freud, Austrian psychiatrist, published "The Aetiology of Hysteria." The paper explains how Freud believes his female patients' neurosis, which he labels hysteria, resulted from sexual abuse as children. Freud named the concept of physical symptoms resulting from childhood trauma: hysterical conversion . Freud hypothesized that in order to cure hysteria the patient must relive the experiences through imagination in the most vivid form while under light hypnosis. However, Freud later changed his theory . His new theory claimed that his patients imagined the instances of sexual abuse, which were instead repressed childhood fantasies . By 1905 Freud retracted the theory of hysteria resulting from repressed childhood fantasies. Freud was also one of the first noted psychiatrist to attribute hysteria to men. He diagnosed himself with hysteria--writing he feared his work exacerbated his condition.

Modern perceptions

For the most part, hysteria does not exist as a medical diagnosis in Western culture and has been replaced by other diagnoses such as conversion or functional disorders. The term hysterical, applied to an individual, can mean that they are emotional, irrationally upset, or frenzied. When applied to a situation that does not involve panic, hysteria means that situation is uncontrollably amusing (the connotation being that it invokes hysterical laughter). Hysteria can also impact groups, medically and colloquially referred to as mass hysteria or mass psychogenic illness. Instances of mass hysteria have been recorded throughout history and continue to occur today.

Dissociative disorder

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Dissociative_disorder 

 

Dissociative disorder
Specialty	Psychiatry, psychology

Dissociative disorders (DD) are conditions that involve disruptions or breakdowns of memory, awareness, identity, or perception. People with dissociative disorders use dissociation as a defense mechanism, pathologically and involuntarily. Some dissociative disorders are triggered by psychological trauma, but dissociative disorders such as depersonalization/derealization disorder may be preceded only by stress, psychoactive substances, or no identifiable trigger at all.

The dissociative disorders listed in the American Psychiatric Association's DSM-5 are as follows:

• Dissociative identity disorder (formerly multiple personality disorder): the alternation of two or more distinct personality states with impaired recall among personality states. In extreme cases, the host personality is unaware of the other, alternating personalities; however, the alternate personalities can be aware of all the existing personalities. This category now includes the old derealization disorder category.
  
• Dissociative amnesia (formerly psychogenic amnesia): the temporary loss of recall memory, specifically episodic memory, due to a traumatic or stressful event. It is considered the most common dissociative disorder amongst those documented. This disorder can occur abruptly or gradually and may last minutes to years depending on the severity of the trauma and the patient.
• Dissociative fugue (formerly psychogenic fugue) is now subsumed under the dissociative amnesia category. It is described as reversible amnesia for personal identity, usually involving unplanned travel or wandering, sometimes accompanied by the establishment of a new identity. This state is typically associated with stressful life circumstances and can be short or lengthy.
• Depersonalization disorder: periods of detachment from self or surrounding which may be experienced as "unreal" (lacking in control of or "outside" self) while retaining awareness that this is only a feeling and not a reality.
•  
• Dissociative seizures also known as psychogenic non-epileptic seizures: seizures that are often mistaken for epilepsy but are not caused by electrical pulses in the brain and are in fact another form of dissociation.
• The old category of dissociative disorder not otherwise specified is now split into two: Other specified dissociative disorder, and unspecified dissociative disorder. These categories are used for forms of pathological dissociation that do not fully meet the criteria of the other specified dissociative disorders, or if the correct category has not been determined.

Both dissociative amnesia and dissociative fugue usually emerge in adulthood and rarely occur after the age of 50. The ICD-10 classifies conversion disorder as a dissociative disorder while the DSM-IV classifies it as a somatoform disorder.

Cause and treatment

Dissociative identity disorder

Cause: Dissociative identity disorder is caused by ongoing childhood trauma that occurs before the ages of six to nine. People with dissociative identity disorder usually have close relatives who have also had similar experiences.

Treatment: Long-term psychotherapy to improve the patients quality of life.

Dissociative amnesia

Cause: A way to cope with trauma. 

Treatment: Psychotherapy (e.g. talk therapy) counseling or psychosocial therapy which involves talking about your disorder and related issues with a mental health provider. Psychotherapy often involves hypnosis (help you remember and work through the trauma); creative art therapy (using creative process to help a person who cannot express his or her thoughts); cognitive therapy (talk therapy to identify unhealthy and negative beliefs/behaviors); and medications (antidepressants, anti-anxiety medications or tranquilizers). These medications help control the mental health symptoms associated with the disorders, but there are no medications that specifically treat dissociative disorders. However, the medication Pentothal can sometimes help to restore the memories. The length of an event of dissociative amnesia may be a few minutes or several years. If an episode is associated with a traumatic event, the amnesia may clear up when the person is removed from the traumatic situation.

Dissociative fugue

Cause: A stressful event that happens in adulthood.

Treatment: Hypnosis is often used to help patient recall true identity and remember events of the past. Psychotherapy is helpful for the person who has traumatic, past events to resolve. Once dissociative fugue is discovered and treated, many people recover quickly. The problem may never happen again.

Depersonalization disorder

Cause: Dissociative disorders usually develop as a way to cope with trauma. The disorders most often form in children subjected to chronic physical, sexual or emotional abuse or, less frequently, a home environment that is otherwise frightening or highly unpredictable; however, this disorder can also acutely form due to severe traumas such as war or the death of a loved one.

Treatment: Same treatment as dissociative amnesia, and same drugs. An episode of depersonalization disorder can be as brief as a few seconds or continue for several years.

Specific psychopharmacology

As mentioned earlier, anti-anxiety, antidepressants and tranquilizers are treatment medications that do not cure, but may help control the symptoms of dissociative disorders.

Diagnosis and prevalence

The lifetime prevalence of dissociative disorders varies from 10% in the general population to 46% in psychiatric inpatients. Diagnosis can be made with the help of structured interviews such as the Dissociative Disorders Interview Schedule (DDIS) and the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D), or with the Dissociative Experiences Scale (DES) which is a self-assessment questionnaire. Some diagnostic tests have also been adapted or developed for use with children and adolescents such as the Children's Version of the Response Evaluation Measure (REM-Y-71), Child Interview for Subjective Dissociative Experiences, Child Dissociative Checklist (CDC), Child Behavior Checklist (CBCL) Dissociation Subscale, and the Trauma Symptom Checklist for Children Dissociation Subscale.

There are problems with classification, diagnosis and therapeutic strategies of dissociative and conversion disorders which can be understood by the historic context of hysteria. Even current systems used to diagnose DD such as the DSM-IV and ICD-10 differ in the way the classification is determined. In most cases mental health professionals are still hesitant to diagnose patients with Dissociative Disorder, because before they are considered to be diagnosed with Dissociative Disorder these patients have more than likely been diagnosed with major depression, anxiety disorder, and most often post-traumatic disorder.

An important concern in the diagnosis of dissociative disorders is the possibility that the patient may be feigning symptoms in order to escape negative consequences. Young criminal offenders report much higher levels of dissociative disorders, such as amnesia. In one study it was found that 1% of young offenders reported complete amnesia for a violent crime, while 19% claimed partial amnesia. There have also been cases in which people with dissociative identity disorder provide conflicting testimonies in court, depending on the personality that is present.

Children and adolescents

Dissociative disorders (DD) are widely believed to have roots in traumatic childhood experience (abuse or loss), but symptomology often goes unrecognized or is misdiagnosed in children and adolescents. There are several reasons why recognizing symptoms of dissociation in children is challenging: it may be difficult for children to describe their internal experiences; caregivers may miss signals or attempt to conceal their own abusive or neglectful behaviors; symptoms can be subtle or fleeting; disturbances of memory, mood, or concentration associated with dissociation may be misinterpreted as symptoms of other disorders.

In addition to developing diagnostic tests for children and adolescents (see above), a number of approaches have been developed to improve recognition and understanding of dissociation in children. Recent research has focused on clarifying the neurological basis of symptoms associated with dissociation by studying neurochemical, functional and structural brain abnormalities that can result from childhood trauma. Others in the field have argued that recognizing disorganized attachment (DA) in children can help alert clinicians to the possibility of dissociative disorders.

Clinicians and researchers also stress the importance of using a developmental model to understand both symptoms and the future course of DDs. In other words, symptoms of dissociation may manifest differently at different stages of child and adolescent development and individuals may be more or less susceptible to developing dissociative symptoms at different ages. Further research into the manifestation of dissociative symptoms and vulnerability throughout development is needed. Related to this developmental approach, more research is required to establish whether a young patient's recovery will remain stable over time.

Current debates and the DSM-5

A number of controversies surround DD in adults as well as children. First, there is ongoing debate surrounding the etiology of dissociative identity disorder (DID). The crux of this debate is if DID is the result of childhood trauma and disorganized attachment. A second area of controversy surrounds the question of whether or not dissociation as a defense versus pathological dissociation are qualitatively or quantitatively different. Experiences and symptoms of dissociation can range from the more mundane to those associated with posttraumatic stress disorder (PTSD) or acute stress disorder (ASD) to dissociative disorders. Mirroring this complexity, it is still being decided whether the DSM-5 will group dissociative disorders with other trauma/stress disorders.

A 2012 review article supports the hypothesis that current or recent trauma may affect an individual's assessment of the more distant past, changing the experience of the past and resulting in dissociative states. However, experimental research in cognitive science continues to challenge claims concerning the validity of the dissociation construct, which is still based on Freudian notions of repression. Even the claimed etiological link between trauma/abuse and dissociation has been questioned. An alternative model proposes a perspective on dissociation based on a recently established link between a labile sleep–wake cycle and memory errors, cognitive failures, problems in attentional control, and difficulties in distinguishing fantasy from reality."

Porphyria

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Porphyria

Porphyria
Left figure is urine on the first day while the right figure is urine after three days of sun exposures showing the classic change in color to purple.
Pronunciation	/pɔːrˈfɪriə/ or /pɔːrˈfaɪriə/
Specialty	Hematology, dermatology, neurology
Symptoms	Depending on subtype–abdominal pain, chest pain, vomiting, confusion, constipation, fever, seizures, blisters with sunlight
Usual onset	Recurrent attacks that last days to weeks
Causes	Usually genetic
Diagnostic method	Blood, urine, and stool tests, genetic testing
Differential diagnosis	Lead poisoning, alcoholic liver disease
Treatment	Depends on type and symptoms
Frequency	1 to 100 in 50,000 people

Porphyria is a group of diseases in which substances called porphyrins build up, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and last a short time. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.

Most types of porphyria are inherited from one or both of a person's parents, and are due to a mutation in one of the genes that make heme. They may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. One type, porphyria cutanea tarda, may also be due to increased iron in the liver, hepatitis C, alcohol, or HIV/AIDS. The underlying mechanism results in a decrease in the amount of heme produced and a build-up of substances involved in making heme. Porphyrias may also be classified by whether the liver or the bone marrow is affected. Diagnosis is typically made by blood, urine, and stool tests. Genetic testing may be done to determine the specific mutation.

Treatment depends on the type of porphyria and a person's symptoms. The treatment of porphyria of the skin generally involves the avoidance of sunlight. The treatment for acute porphyria may involve giving intravenous heme or a glucose solution. Rarely, a liver transplant may be carried out.

The precise frequency of porphyria is unclear but it is estimated that it affects between 1 and 100 per 50,000 people. Rates vary around the world. Porphyria cutanea tarda is believed to be the most common type. The disease was described as early as 370 BC by Hippocrates. The underlying mechanism was first described by Felix Hoppe-Seyler in 1871. The name porphyria is from the Greek πορφύρα, porphyra, meaning "purple", a reference to the color of the urine that may occur during an attack.

Signs and symptoms

A skin rash in a person with porphyria

Acute porphyrias

The acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD) and hereditary coproporphyria (HCP). These diseases primarily affect the nervous system, resulting in episodic crises known as acute attacks. The major symptom of an acute attack is abdominal pain, often accompanied by vomiting, hypertension (elevated blood pressure), and tachycardia (an abnormally rapid heart rate).

The most severe episodes may involve neurological complications: typically motor neuropathy (severe dysfunction of the peripheral nerves that innervate muscle), which leads to muscle weakness and potentially to quadriplegia (paralysis of all four limbs) and central nervous system symptoms such as seizures and coma. Occasionally, there may be short-lived psychiatric symptoms such as anxiety, confusion, hallucinations, and, very rarely, overt psychosis. All these symptoms resolve once the acute attack passes. 

Given the many presentations and the relatively low occurrence of porphyria, patients may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for Guillain–Barré syndrome, and porphyria testing is commonly recommended in those situations.

Chronic porphyrias

The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). None of these are associated with acute attacks; their primary manifestation is with skin disease. For this reason, these four porphyrias—along with two acute porphyrias, VP and HCP, that may also involve skin manifestations—are sometimes called cutaneous porphyrias.

Skin disease is encountered where excess porphyrins accumulate in the skin. Porphyrins are photoactive molecules, and exposure to light results in promotion of electrons to higher energy levels. When these return to the resting energy level or ground state, energy is released. This accounts for the property of fluorescence typical of the porphyrins. This causes local skin damage.

Two distinct patterns of skin disease are seen in porphyria:

• Immediate photosensitivity. This is typical of XLDPP and EPP. Following a variable period of sun exposure—typically about 30 minutes—patients complain of severe pain, burning, and discomfort in exposed areas. Typically, the effects are not visible, though occasionally there may be some redness and swelling of the skin.
• Vesiculo-erosive skin disease. This—a reference to the characteristic blistering (vesicles) and open sores (erosions) noted in patients—is the pattern seen in CEP, PCT, VP, and HCP. The changes are noted only in sun-exposed areas such as the face and back of the hands. Milder skin disease, such as that seen in VP and HCP, consists of increased skin fragility in exposed areas with a tendency to form blisters and erosions, particularly after minor knocks or scrapes. These heal slowly, often leaving small scars that may be lighter or darker than normal skin. More severe skin disease is sometimes seen in PCT, with prominent lesions, darkening of exposed skin such as the face, and hypertrichosis: abnormal hair growth on the face, particularly the cheeks. The most severe disease is seen in CEP and a rare variant of PCT known as hepatoerythropoietic porphyria (HEP); symptoms include severe shortening of digits, loss of skin appendages such as hair and nails, and severe scarring of the skin with progressive disappearance of ears, lips, and nose. Patients may also show deformed, discolored teeth or gum and eye abnormalities.

Cause

The porphyrias are generally considered genetic in nature.

Genetics

Subtypes of porphyrias depend on which enzyme is deficient. 

Porphyria type	Deficient enzyme	Type of porphyria	Inheritance	Symptoms	Prevalence
X-linked dominant protoporphyria (XLDPP)	5-aminolevulinate (ALA) synthase (ALAS)	Erythropoietic	X-linked dominant	Photosensitivity, cirrhosis	Rare; about 50 cases reported
Aminolevulinate dehydratase deficiency porphyria (ALADP)	5-aminolevulinate dehydratase (ALAD)	Hepatic	Autosomal recessive	Abdominal pain, neuropathy	Extremely rare; fewer than 10 cases ever reported.
Acute intermittent porphyria (AIP)	Hydroxymethylbilane synthase (HMBS) formerly porphobilinogen deaminase (PBGD)	Hepatic	Autosomal dominant	Periodic abdominal pain, peripheral neuropathy, psychiatric disorders, tachycardia
Congenital erythropoietic porphyria (CEP)	uroporphyrinogen synthase (UROS)	Erythropoietic	Autosomal recessive	Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, splenomegaly	1 in 1,000,000 or less.
Porphyria cutanea tarda (PCT)	uroporphyrinogen decarboxylase (UROD)	Hepatic	Approximately 80% sporadic, 20% Autosomal dominant	Photosensitivity with vesicles and bullae	1 in 10,000
Hereditary coproporphyria (HCP)	coproporphyrinogen oxidase (CPOX)	Hepatic	Autosomal dominant	Photosensitivity, neurologic symptoms, colic	1 in 500,000
Harderoporphyria	coproporphyrinogen oxidase (CPOX)	Erythropoietic	Autosomal recessive	Jaundice, anemia, enlarged liver and spleen, often neonatal. Photosensitivity later.	Extremely rare; fewer than 10 cases ever reported.
Variegate porphyria (VP)	protoporphyrinogen oxidase (PPOX)	Hepatic	Autosomal dominant	Photosensitivity, neurologic symptoms, developmental delay	1 in 300 in South Africa 1 in 75,000 in Finland
Erythropoietic protoporphyria (EPP)	Ferrochelatase (FECH)	Erythropoietic	Autosomal dominant	Photosensitivity with skin lesions. Gallstones, mild liver dysfunction	1 in 75,000–200,000

In the autosomal recessive types, if a person inherits a single gene they may become a carriers. Generally they do not have symptoms, but may pass the gene onto offspring.

Triggers

Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include:

• Sulfonamides, including sulfadiazine, sulfasalazine and trimethoprim/sulfamethoxazole.
• Sulfonylureas like glibenclamide, gliclazide and glimepiride, although glipizide is thought to be safe.
• Barbiturates including thiopental, phenobarbital, primidone, etc.
• Systemic treatment with antifungals including fluconazole, griseofulvin, ketoconazole and voriconazole. (Topical use of these agents is thought to be safe due to minimal systemic absorption.)
• Certain antibiotics like rifapentine, rifampicin, rifabutine, isoniazid, nitrofurantoin and, possibly, metronidazole.
• Ergot derivatives including dihydroergotamine, ergometrine, ergotamine, methysergide, etc.
• Certain antiretroviral medications (e.g. indinavir, nevirapine, ritonavir, saquinavir, etc.)
• Progestogens
• Some anticonvulsants including: carbamazepine, ethosuximide, phenytoin, topiramate, valproate.
• Some painkillers like dextropropoxyphene, ketorolac, metamizole, pentazocine
• Some cancer treatments like bexarotene, busulfan, chlorambucil, estramustine, etoposide, flutamide, idarubicin, ifosfamide, irinotecan, ixabepilone, letrozole, lomustine, megestrol, mitomycin, mitoxantrone, paclitaxel, procarbazine, tamoxifen, topotecan
• Some antidepressants like imipramine, phenelzine, trazodone
• Some antipsychotics like risperidone, ziprasidone
• Some retinoids used for skin conditions like acitretin and isotretinoin
• Miscellaneous others including: cocaine, methyldopa, fenfluramine, disulfiram, orphenadrine, pentoxifylline, and sodium aurothiomalate.

Pathogenesis

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes. 

The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells.

Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias; most heme synthesis enzymes—even dysfunctional enzymes—have enough residual activity to assist in heme biosynthesis. The principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces).

There are eight enzymes in the heme biosynthetic pathway, four of which—the first one and the last three—are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria. 

The hepatic porphyrias are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain, and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth. 

Variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. Hereditary coproporphyria, which is characterized by a deficiency in coproporphyrinogen oxidase, coded for by the CPOX gene, may also present with both acute neurologic attacks and cutaneous lesions. All other porphyrias are either skin- or nerve-predominant.

Diagnosis

Porphyrin studies

Porphyria is diagnosed through biochemical analysis of blood, urine, and stool. In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway. In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to hereditary tyrosinemia type I. In cases of mercury- or arsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III, and pre-coproporphyrin.

Repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria, as levels may be normal or near-normal between attacks. The urine screening test has been known to fail in the initial stages of a severe, life-threatening attack of acute intermittent porphyria.

Up to 90% of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and may require DNA or enzyme testing. The exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria.

As most porphyrias are rare conditions, general hospital labs typically do not have the expertise, technology, or staff time to perform porphyria testing. In general, testing involves sending samples of blood, stool, and urine to a reference laboratory. All samples to detect porphyrins must be handled properly. Samples should be taken during an acute attack; otherwise a false negative result may occur. Samples must be protected from light and either refrigerated or preserved.

If all the porphyrin studies are negative, one must consider pseudoporphyria. A careful medication review often will find the cause of pseudoporphyria.

Additional tests

Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver. Basic biochemical tests may assist in identifying liver disease, hepatocellular carcinoma, and other organ problems.

Management

Acute porphyria

Carbohydrate administration

Often, empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal. A high-carbohydrate diet is typically recommended; in severe attacks, a dextrose 10% infusion is commenced, which may aid in recovery by suppressing heme synthesis, which in turn reduces the rate of porphyrin accumulation. However, this can worsen hyponatraemia and should be done with extreme caution as it can prove fatal.

Heme analogs

Hematin (trade name Panhematin) and heme arginate (trade name NormoSang) are the drugs of choice in acute porphyria, in the United States and the United Kingdom, respectively. These drugs need to be given very early in an attack to be effective; effectiveness varies amongst individuals. They are not curative drugs but can shorten attacks and reduce the intensity of an attack. Side effects are rare but can be serious. These heme-like substances theoretically inhibit ALA synthase and hence the accumulation of toxic precursors. In the United Kingdom, supplies of NormoSang are kept at two national centers; emergency supply is available from St Thomas's Hospital, London. In the United States, Lundbeck manufactures and supplies Panhematin for infusion.

Heme arginate (NormoSang) is used during crises but also in preventive treatment to avoid crises, one treatment every 10 days.

Any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin, heme arginate, or even tin mesoporphyrin, as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe, progressing to bulbar paresis and respiratory paralysis.

Cimetidine

Cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis.

Symptom control

Pain is severe, frequently out of proportion to physical signs, and often requires the use of opiates to reduce it to tolerable levels. Pain should be treated as early as medically possible. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot baths and showers may lessen nausea temporarily, though caution should be used to avoid burns or falls.

Early identification

It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an alert bracelet or other identification at all times. This is in case they develop severe symptoms, or in case of accidents where there is a potential for drug exposure, and as a result they are unable to explain their condition to healthcare professionals. Some drugs are absolutely contraindicated for patients with any form of porphyria.

Neurologic and psychiatric disorders

Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen. Intestinal pseudo-obstruction, ileus, intussusception, hypoganglionosis, and encopresis in children have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, Gabapentin is known to improve outcome.

Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturates especially must be avoided. Some benzodiazepines are safe and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control. Gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain. Magnesium sulfate and bromides have also been used in porphyria seizures; however, development of status epilepticus in porphyria may not respond to magnesium alone. The addition of hematin or heme arginate has been used during status epilepticus.

Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of antidepressants. Some psychotropic drugs are porphyrinogenic, limiting the therapeutic scope. Other psychiatric symptoms such as anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis may occur.

Underlying liver disease

Some liver diseases may cause porphyria even in the absence of genetic predisposition. These include hemochromatosis and hepatitis C. Treatment of iron overload may be required.

Patients with the acute porphyrias (AIP, HCP, VP) are at increased risk over their life for hepatocellular carcinoma (primary liver cancer) and may require monitoring. Other typical risk factors for liver cancer need not be present.

Hormone treatment

Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives and luteinizing hormones to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. Androgens and fertility hormones have also triggered attacks. In 2019, givosiran was approved in the United States for the treatment of acute hepatic porphyria.

Erythropoietic porphyria

These are associated with accumulation of porphyrins in erythrocytes and are rare. 

The pain, burning, swelling, and itching that occur in erythropoietic porphyrias generally require avoidance of bright sunlight. Most kinds of sunscreen are not effective, but SPF-rated long-sleeve shirts, hats, bandanas, and gloves can help. Chloroquine may be used to increase porphyrin secretion in some EPs. Blood transfusion is occasionally used to suppress innate heme production.

The rarest is congenital erythropoietic porphyria (C.E.P.), otherwise known as Gunther's disease. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of Type 1 porphyrins, and later hypertrichosis. Hemolytic anemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment. A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available.

In December 2014, afamelanotide received authorization from the European Commission as a treatment for the prevention of phototoxicity in adult patients with EPP.

Epidemiology

Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the United States. The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.

Porphyrias have been detected in all races and in multiple ethnic groups on every continent. There are high incidence reports of AIP in areas of India and Scandinavia. More than 200 genetic variants of AIP are known, some of which are specific to families, although some strains have proven to be repeated mutations.

History

The underlying mechanism was first described by Felix Hoppe-Seyler in 1871, and acute porphyrias were described by the Dutch physician Barend Stokvis in 1889.

The links between porphyrias and mental illness have been noted for decades. In the early 1950s, patients with porphyrias (occasionally referred to as "porphyric hemophilia") and severe symptoms of depression or catatonia were treated with electroshock therapy.

Vampires and werewolves

Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon certain perceived similarities between the condition and the folklore.

In January 1964, L. Illis's 1963 paper, "On Porphyria and the Aetiology of Werewolves," was published in Proceedings of the Royal Society of Medicine. Later, Nancy Garden argued for a connection between porphyria and the vampire belief in her 1973 book, Vampires. In 1985, biochemist David Dolphin's paper for the American Association for the Advancement of Science, "Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends," gained widespread media coverage, popularizing the idea.

The theory has been rejected by a few folklorists and researchers as not accurately describing the characteristics of the original werewolf and vampire legends or the disease, and as potentially stigmatizing people with porphyria.

A 1995 article from the Postgraduate Medical Journal (via NIH) explains:

As it was believed that the folkloric vampire could move about freely in daylight hours, as opposed to the 20th century variant, congenital erythropoietic porphyria cannot readily explain the folkloric vampire but may be an explanation of the vampire as we know it in the 20th century. In addition, the folkloric vampire, when unearthed, was always described as looking quite healthy ("as they were in life"), while due to disfiguring aspects of the disease, sufferers would not have passed the exhumation test. Individuals with congenital erythropoietic porphyria do not crave blood. The enzyme (hematin) necessary to alleviate symptoms is not absorbed intact on oral ingestion, and drinking blood would have no beneficial effect on the sufferer. Finally, and most important, the fact that vampire reports were literally rampant in the 18th century, and that congenital erythropoietic porphyria is an extremely rare manifestation of a rare disease, makes it an unlikely explanation of the folkloric vampire.

Notable cases

George III in his coronation robes

 

Mary, Queen of Scots c. 1578.

• King George III. The mental illness exhibited by George III in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis. The first, written in 1855, thirty-five years after his death, concluded that he had acute mania. M. Guttmacher, in 1941, suggested manic-depressive psychosis as a more likely diagnosis. The first suggestion that a physical illness was the cause of King George's mental derangement came in 1966, in a paper called "The Insanity of King George III: A Classic Case of Porphyria", with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia". The papers, by a mother/son psychiatrist team, were written as though the case for porphyria had been proven, but the response demonstrated that many experts, including those more intimately familiar with the manifestations of porphyria, were unconvinced. Many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. The theory is treated in Purple Secret, which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have had it. In 2005, it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria. This study found high levels of arsenic in King George's hair. In 2010, one analysis of historical records argued that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources. The mental illness of George III is the basis of the plot in The Madness of King George, a 1994 British film based upon the 1991 Alan Bennett play, The Madness of George III. The closing credits of the film include the comment that the King's symptoms suggest that he had porphyria and notes that the disease is "periodic, unpredictable, and hereditary".

• Descendants of George III. Among other descendants of George III theorized by the authors of Purple Secret to have had porphyria (based on analysis of their extensive and detailed medical correspondence) were his great-great-granddaughter Princess Charlotte of Prussia (Emperor William II's eldest sister) and her daughter Princess Feodora of Saxe-Meiningen. They uncovered better evidence that George III's great-great-great-grandson Prince William of Gloucester was reliably diagnosed with variegate porphyria.

• Mary, Queen of Scots. It is believed that Mary, Queen of Scots, King George III's ancestor, also had acute intermittent porphyria, although this is subject to much debate. It is assumed she inherited the disorder, if indeed she had it, from her father, James V of Scotland. Both father and daughter endured well-documented attacks that could fall within the constellation of symptoms of porphyria.

Maria I of Portugal in a c. 1790s portrait attributed to Giuseppe Troni or Thomas Hickey.

• Maria I of Portugal. Maria I—known as "Maria the Pious" or "Maria the Mad" because of both her religious fervor and her acute mental illness, which made her incapable of handling state affairs after 1792 – is also thought to have had porphyria. Francis Willis, the same physician who treated George III, was even summoned by the Portuguese court but returned to England after the court limited the treatments he could oversee. Contemporary sources, such as Secretary of State for Foreign Affairs Luís Pinto de Sousa Coutinho, noted that the queen had ever-worsening stomach pains and abdominal spasms: hallmarks of porphyria.

• Vlad III. Vlad III was also said to have had acute porphyria, which may have started the notion that vampires were allergic to sunlight.

• Vincent van Gogh. Other commentators have suggested that Vincent van Gogh may have had acute intermittent porphyria.

• King Nebuchadnezzar of Babylon. The description of this king in Daniel 4 suggests to some that he had porphyria.

• Physician Archie Cochrane. He was born with porphyria, which caused health problems throughout his life.

• Paula Frías Allende. The daughter of the Chilean novelist Isabel Allende, she fell into a porphyria-induced coma in 1991, which inspired Isabel to write the memoir Paula, dedicated to her.