THE PORPHYRIAS

The porphyrias form a rare heterogeneous group of inherited disorders of haem synthesis. This leads to an overproduction of the intermediate com-pounds called porphyrins (Fig. 15.3). In porphyrias the excess production of porphyrins occurs within the liver (hepatic porphyria) or in the bone marrow (erythropoietic porphyria), but porphyrias can also be classified in terms of clinical presentation as acute or non-acute (Table 15.13). Acute porphyrias usually produce neuropsychiatric problems and are associated with excess production and urinary excretion of S-aminolaevulinic acid (S-ALA) and porphobilinogen. These metabolites are not increased in the non-acute porphyrias.

Acute intermittent porphyria

This is an autosomal dominant disorder caused by a defect at the level of porphobilinogen deaminase. It is the commonest of the acute porphyrias. Presentation is in early adult life, and women are affected more than men.

Clinical features

Abdominal pain, vomiting and constipation are the most common presenting features, occurring in 90% of patients (mimicking an acute abdomen, espe-cially as there may be fever and leucocytosis). Additional features include polyneuropathy (especially motor), hypertension, tachycardia and neuro-psychiatric disorder (fits, depression, anxiety and frank psychosis). The

Fig. 15.3 Pathways in porphyrin metabolism.

Table 15.13 The classification of the porphyrias
  Hepatic Erythropoietic
Acute Acute intermittent porphyria
Variegate porphyria
Hereditary coproporphyria
 
Non-acute Porphyria cutanea tarda Congenital porphyria
Erythropoietic protoporphyria

urine may turn red or brown on standing. Attacks may be precipitated by alcohol and a variety of drugs, especially those such as barbiturates, which are enzyme-inducing drugs and increase S-ALA synthetase activity.

Investigations

During an attack there may be a neutrophil leucocytosis, abnormal liver biochemistry and a raised urea.

The diagnosis is made during an attack by demonstrating increased urinary excretion of porphobilinogen. Erythrocyte porphobilinogen deaminase may be measured between attacks or, in some cases, urinary porpho-bilinogen remains high.

Management

Abdominal pain is severe and may require opiate analgesia. A high carbohy-drate intake (oral or intravenous glucose) must be maintained because this depresses S-ALA synthetase activity. Haem arginate is a stable preparation of haem and is given intravenously during an acute attack. Haem inhibits ALA synthetase (Fig. 15.2) and hence reduces levels of the intermediate precursors.

Other porphyrias

Porphyria cutanea tarda (PCT) has both sporadic and inherited forms (auto-somal dominant) that are indistinguishable clinically. It presents with a bullous skin eruption on exposure to light or minor trauma. The eruption heals with scarring. Many patients with sporadic PCT have underlying chronic liver disease (particularly due to alcohol or hepatitis C infection).

Variegate porphyria and hereditary coproporphyria present with features similar to those of acute intermittent porphyria, together with the cutaneous features of PCT.

The erythropoietic porphyrias are very rare and present with photosensitive skin lesions.

AMYLOIDOSIS

This is a heterogeneous group of disorders characterized by extracellular deposition of an insoluble fibrillar protein called amyloid. Amyloidosis is acquired or hereditary, and may be localized or systemic. Clinical features are the result of amyloid deposits affecting the normal structure and function of the affected tissue. The diagnosis of amyloidosis is usually made with Congo red staining of a biopsy of affected tissues. In systemic amyloid a simple rectal biopsy may be used for histological diagnosis. Amyloid deposits stain red and show green fluorescence in polarized light. Scintigraphy using 123I-labelled serum amyloid P component is being increasingly employed for assessment.

The features of some systemic amyloid types are shown in Table 15.14.

Localized amyloid deposits occur in the brain of patients with Alzheimer's disease and in the joints of patients on long-term dialysis.

THERAPEUTICS

Oral antidiabetic drugs

Metformin

Mechanism of action

Activates AMp-kinase, which is involved in metabolism of the membrane glucose transporter, GLUT4, and fatty acid oxidation. Increases glucose

Table 15.14 Classification of the more common types of amyloid and amyloidosis

Type

Fibril protein precursor

Clinical syndrome

AL

Monoclonal immunoglobulin light chains

Associated with myeloma, Waldenstrồm’s macroglobulinaemia and non-Hodgkin lymphoma. Presents with cardiac failure, nephrotic syndrome, carpal tunnel syndrome and macroglossia (large tongue)

ATTR (familial)

Abnormal transthyretin (plasma carrier protein)

Neuropathy and cardiomyopathy

AA

Protein A, a precursor of serum amyloid A (an acute-phase reactant)

Occurs with chronic infections (e.g. TB), inflammation (e.g. rheumatoid arthritis) and malignancy (e.g. Hodgkin’s disease). Presents with proteinuria and hepatosplenomegaly

transport into cells, decreases hepatic gluconeogenesis and increases insulin sensitivity.

Indications

Drug of first choice in overweight patients in whom strict dieting has failed to control diabetes. Also used in combination with sulphonylureas, pio-glitazone, repaglinide, nateglinide or insulin if diabetes is inadequately con-trolled with metformin alone. Also improves fertility and weight reduction in patients with polycystic ovary syndrome.

Preparations and dose

Metformin Tablets: 500 mg, 850 mg.

500 mg once daily initially, then titrate upwards in weekly increments to three times a day with meals, or 850 mg every 12 hours; maximum 3 g daily in divided doses.

Side-effects

Anorexia, nausea, vomiting, diarrhoea (usually transient), abdominal pain, metallic taste, rarely type B (non-hypoxic) lactic acidosis (mortality of 3050%), B12 deficiency (decreased absorption). Hypoglycaemia does not usually occur with metformin.

Cautions/contraindications

Contraindicated in severe renal impairment (eGFR < 30 mL/min/1.73 m2) because of increased risk of lactic acidosis. Withdraw if tissue hypoxia likely (e.g. sepsis, respiratory failure, recent myocardial infarction, hepatic impair-ment), use of iodine-containing X-ray contrast media (do not restart until renal function returns to normal) and use of general anaesthesia (suspend met-formin 2 days before surgery and restart when renal function returns to normal).

Sulphonylureas

Mechanism of action

Augment insulin secretion.

Indications

Patients with type 2 diabetes mellitus who are not overweight, or in whom metformin is contraindicated or not tolerated.

Preparations and dose

Several sulphonylureas are available and choice is determined by side-effects and the duration of action as well as the patient's age and renal function. Glibenclamide is long acting and associated with a greater risk of hypogly-caemia and should be avoided in the elderly. Gliclazide and tolbutamide are shorter acting and are a better choice.

Glibenclamide Tablets: 2.5 mg, 5 mg.

Initially 5 mg daily with or immediately after breakfast, adjusted according to response; maximum 15 mg daily.

Tolbutamide Tablets: 500 mg.

0.5-1.5 g (max. 2g) daily in divided doses with or immediately after breakfast.

Gliclazide Tablets: 80 mg.

Initially 40-80 mg daily, adjusted according to response up to 160 mg as a single dose or 320 mg daily in divided doses.

Side-effects

Generally mild and infrequent and include gastrointestinal disturbances such as nausea, vomiting, diarrhoea and constipation. May encourage weight gain. Sulphonylurea-induced hypoglycaemia may persist for many hours and must always be treated in hospital. Occasionally cholestatic jaundice, hepatitis, allergic skin reactions and blood disorders.

Cautions/contraindications

Use short-acting form in renal impairment. Avoid sulphonylureas in severe renal and hepatic impairment, and in porphyria. Contraindicated in breast feeding, and substitute insulin during pregnancy.

Treatment of hypoglycaemia

Initially glucose 10-20 g (2-4 teaspoons sugar, 3-6 sugar lumps, 50100 mL fizzy drink) is given by mouth. If sugar cannot be given by mouth (e.g. unconscious patient), glucose or glucagon can be given by injection.

Mechanism of action

Glucagon mobilizes glycogen stored in the liver.

Indications

Acute hypoglycaemia where glucose cannot be given either by mouth or intravenously.

Preparations and dose

Glucagon GlucaGen® Hypokit 1 mg vial with prefilled syringe containing water for injection.

By subcutaneous, intramuscular, or intravenous injection 1 mg.

Side-effects

Nausea, vomiting, abdominal pain, hypokalaemia, hypotension, hypersensi-tivity reactions.

Cautions/contraindications

Phaeochromocytoma.

Lipid-lowering drugs

Statins

Mechanism of action

Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme involved in cholesterol synthesis. More effective at lowering LDL-cholesterol than other classes of drugs but less effective than the fibrates in reducing triglycerides.

Indications

Secondary prevention of coronary and cardiovascular events in patients with history of angina or myocardial infarction, peripheral artery disease, non-haemorrhagic stroke, transient ischaemic attack. Primary prevention of coronary events in patients at increased risk of coronary heart disease such as inherited dyslipidaemias or a 10-year cardiovascular risk of 20% or more calculated using tables such as the Joint British Societies Coronary Risk Prediction Chart in the British National Formulary.

Preparations and dose

Atorvastatin Lipitor® tablets: 10 mg, 20 mg, 40 mg, 80 mg.

10 mg once daily at night increased at intervals of at least 4 weeks to 40 mg once daily. Maximum 80 mg daily.

Simvastatin Tablets: 10 mg, 20 mg, 40 mg, 80 mg.

10 mg at night, increased at intervals of at least 4 weeks up to 80 mg at night.

Side-effects

Reversible myositis/myopathy - ask patients to report unexplained muscle pain, measure serum creatine kinase (CK) and stop statin if CK >5 X upper limit of normal. Diagnose rhabdomyolysis if CK >10 X upper limit of normal. In this case check serum creatinine (may be acute kidney injury) and urine myoglobin. Altered liver biochemistry - liver biochemistry should be meas-ured before and within 3 months and at 12 months of starting treatment, unless indicated sooner by signs or symptoms suggestive of hepatotoxicity. Stop treatment if serum transaminase concentration persistently raised to 3 times the upper limit of the reference range. Gastrointestinal effects including abdominal pain, diarrhoea, flatulence and vomiting.

Cautions/contraindications

Contraindicated in acute liver disease (acute viral hepatitis, alcoholic hepati-tis) pregnancy (adequate contraception during treatment and for 1 month afterwards), breast feeding and personal or family history of muscle disorders. Increased risk of myositis and rhabdomyolysis if statins are given with a fibrate, ezetimibe, ciclosporin, digoxin, warfarin, erythromycin and ketoconazole.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology



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