Central pontine myelinolysis

 Disease class: brain diseases, Metabolic

Disease class: Demyelinating diseases

 

Consequences

• Locked-in syndrome

 

Causes

• Iatrogenic: Aggressive correction of hyponatraemia. Sodium restoration (e.g. by an infusion of sodium chloride) must be very slow and gradual. Specialist advice should be sought.

Hyperlactataemia

Disease class: Metabolic diseases

Wernicke encephalopathy

Disease class: brain diseases, Metabolic 

 

Also known as 

• WE 
• Wernicke's disease

When WE occurs with Korsakoff syndrome the diagnosis is Wernicke-Korsakoff syndrome.

 

Pathophysiology

It is caused by vitamin B1 (thiamine) deficiency.

 

Symptoms

• Unsteady gait 
• Blurred vision
• Confusion

 

Signs

• Ophthalmoplegia
• Ataxia

 

Risk factors

• Chronic alcohol misuse
• Poverty
• Psychiatric disorders

Megaloblastic anaemia

Disease class: Macrocytic anaemia

The macrocytic red cells show signs of immaturity. They have failed to mature fully from erythroblasts into erythocytes.

 

Causes

• Folic acid deficiency
• Vitamin B12 deficiency 
• Pernicious anaemia
• Vitamin B12 deficiency anaemia

Osteoporosis

Disease class: bone diseases, Metabolic

Osteitis deformans

Disease class: Bone diseases

Also known as

•  Paget's disease of bone

This is a disease of bone metabolism.
After osteoporosis, this is the second most common bone disorder.
There is a wide range of severity. Most cases are identified by incidental diagnosis while investigating an unrelated disease.

 

Pathophysiology

There is increased osteoclastic activity and dysfunctional bone remodelling.

 

Causes

• Unknown

 

Risk factors

• Genetic factors
• Advanced age (10% of patients over 80 years old have Paget's disease of bone)

 

Symptoms

Paget's only causes symptoms in approximately 35% of patients at the point of first diagnosis.

• Bone pain 
• Headache
• Frequent bone fractures
• Leg bowing
• Hearing loss

 

Signs

• Deformity of the bones, especially the long leg bones, vertebral column (spine), pelvic bones, and skull bones
• Increased hat size
• Warmth of affected areas

 

Complications

• Osteoarthritis
• Heart failure (rarely seen in severe cases): occurs due to increasing systemic vascular resistance introduced by abnormal vascularity in the affected bones.

 

Epidemiology

• More common in men than women (3:2)
• Most common in patients with British ancestry
• Prevalence: 1.5 to 8.0% of the population

 

Management

• There is no curative treatment for this disease.
• The symptoms can be reduced with bisphosphonates and analgesics.
• Surgery may be helpful in some situations.

Familial hypercholesterolaemia

Phenylketonuria

Also known as PKU.

Gilbert's syndrome

Also known as hyperbilirubinemia type 1

Hereditary haemochromatosis

Disease class: Iron overload

A disease in which cirrhosis of the liver, enlargement of the spleen, pigmentation of the skin, and diabetes mellitus are associated with the abnormal and excessive deposit in the organs of the body of the iron-containing pigment, haemosiderin. It is caused by an increase in the amount of iron absorbed from the gastrointestinal tract.

Wilson's disease

Organ system: The digestive system

Organ: The liver

Disease class: Nervous system heredodegenerative disorders

Disease class:  Liver diseases

Also known as hepatolenticular degeneration.

This is a familial disease in which there is an increased accumulation of copper in the liver, brain, and other tissues including the kidneys.

Its main  manifestation is the development of tremor and rigidity, with difficulty in speech.

In many cases there is improvement following treatment with dimercaprol, penicillamine, or trientine dihydrochloride; these substances cause an increased excretion of copper.

 

Signs

• A brown ring on the edge of the cornea (Kayser–Fleischer ring)

Acute intermittent porphyria

Also known as AIP.
Many historians believe that this condition is a potential explanation for "the madness of King George".

AIP causes acute intermittent attacks of symptoms. An attack can result in permanent disability or death.

 

Pathophysiology

In AIP there is a defective porphobilinogen deaminase gene. This results in accumulation of porphobilinogen in the cytoplasm, causing neurotoxic effects. The CNS is relatively protected due to the blood-brain barrier. The autonomic and peripheral nervous system are vulnerable, resulting in abdominal pain, tachycardia, paresis etc. 

 

Features of an acute attack

• Gastrointestinal
• Abdominal pain
• Vomiting 
• Constipation 
• Neuropsychiatric
• Peripheral neuropathy
• Seizures
• Psychosis 
• Cardiovascular
• Hypertension
• Tachycardia
• Shock
• Other
• Fever
• Hyponatraemia
• Hypokalaemia
• Proteinuria
• Urinary porphobilinogens
• Discoloured urine 

• Rarely
• Bulbar paralysis
• Respiratory paralysis 

 

Genetics

• Low-penetrance autosomal dominant 
• Porphobilinogen deaminase gene
• 28% have no family history (caused by de novo mutations) 
• 10% with the defective gene have neurovisceral symptoms

 Triggers

• Infection
• Starvation, nil by mouth
• Reproductive hormones (pregnancy, pre-menstrual) 
• Smoking 
• Anaesthesia
• Cytochrome P450 enzyme inducers
• Disruptions of porphyrin metabolism
• Alcohol
• Lead poisoning
• Iron deficiency
• Drugs
• Diclofenac
• Alcohol
• Oral contraceptive pill & HRT
• Tricyclic antidepressants
• Benzodiazepines
• Anaesthetic agents (barbituates, halothane) 
• Antibiotics (cephalosporins, sulphonamides, macrolides, tetracyclines, rifampicin, trimethoprim, chloramphenicol, metronidazole). 
• Metoclopramide
• ACE-inhibitors
• Ca ²⁺ channel blockers
• Statins
• Anticonvulsants
• Furosemide
• Sulphonylureas
• Lidocaine
• Gold salts
• Antihistamines
• Amphetamines

 

Epidemiology

• Attacks are more common in women
• Attacks are more common in those aged 18-40
• This is the most common form of porphyria
• Prevalence in UK: 1-2 per 100,000 

 

Diagnostics

• During an attack, urine porphobilinogen is raised. The urine may turn deep red on standing. 
• In 50%, urine porphobilinogen is raised between attacks.
• Faecal porphyrin levels are normal.
• No cutaneous photosensitivity. 
• Beware: Can mimic acute surgical abdomen (colic, vomiting, fever, leukocytosis). Anaesthesia use (for surgery) could cause a disaster. 

 

Management of an acute attack

• Remove precipitants
• IV fluids to correct electrolyte imbalance
• High carbohydrate intake
• IV haematin to inhibit porphyrin synthesis.
• Nausea control with prochlorperazine
• Sedation with chlorpromazine 
• Pain control with opiate or opioid analgesia (avoid oxycodone)
• Seizure control with diazepam
• Tachycardia and hypertension treatment with a beta-blocker

 

Long-term management

• Avoid triggers
• Medical identification tag: wrist bracelet, neck pendant and/or card, to warn medics about porphyria. 
• Genetic counselling

Gout

Disease class: Arthritis

Disease class: Crystal arthropathies
Disease class: Rheumatic diseases

This is a cause of inflammatory arthritis.

Pathogenesis

• There is an accumulation of uric acid crystals in the joint space.

Porphyrias

Disease class: Metabolic diseases

Types

• porphyria, Erythropoietic
• porphyrias, Hepatic

The porphyrias are a group of rare metabolic disorders, characterised by dysfunctional biosynthesis of haem, the core protein of haemoglobin. 

 

Etymology

The name porphyria comes from the Greek πορφύρα (porphúra) meaning purple. This is because urine may turn red-purple during a porphyria attack, due to accumulation of these precursor substrates.

 

Pathophysiology

Haem production is the result of a long path of metabolic processes. Each step in the path is catalysed by an enzyme. The rate of conversion from substrate to product is determined by the enzyme activity. This means the rate of substrate removal is determined by enzyme activity. Here is a (very) simplified pathway:

Porphyrin precursors >1> porphyrins >2> haem

Each porphyria gene produces an enzyme with insufficient activity. This means that the substrate for that particular enzyme accumulates, since it is being produced faster than it is being removed. 

If step 1 is faulty, there will be too many porphyrin precursors since their rate of conversion is too low. These accumulate in the body and they induce photosensitivity and toxic radical formation. 

If step 2 is faulty, there will be normal levels of precursors, but too many porphyrins. These accumulate in the body and cause neurovisceral symptoms.

 

Acute porphyrias

In these three diseases, there is an accumulation of the neurotoxic porphyrin precursors. They are autosomal dominant.

• Acute intermittent porphyria  

The following two diseases feature photosensitive blistering skin lesions and/or acute neurovisceral crises.

• Variegate porphyria 
• Hereditary coproporphyria 

 

Non-acute porphyrias  

In these diseases, there is an accumulation of porphyrins but not porphyrin precursors. They feature cutaneous photosensitivity and associated skin manifestations. There are no neurovisceral symptoms.

• Porphyria cutanea tarda 
• Erythropoietic protoporphyria 
• Congenital erythropoietic porphyria 

 

Acquired disturbances of porphyrin metabolism

• Alcohol
• Iron deficiency
• Lead poisoning