TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS

Alcoholic cirrhosis

See alcoholic liver disease (p. 174).

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic disorder in which there is progres-sive destruction of intrahepatic bile ducts causing cholestasis, eventually leading to cirrhosis.

Epidemiology

It affects predominantly women in the age range 40-50 years.

Aetiology

An inherited abnormality of immunoregulation, leads to a T lymphocyte medi-ated attack on bile duct epithelial cells. It is thought that disease expression results from an environmental trigger, possibly infective, in a genetically susceptible individual. Antimitochondrial antibodies (AMAs) are present in most (>95%) patients, but their role in disease pathogenesis is unclear.

Clinical features

Pruritus, with or without jaundice, is the single most common presenting complaint. In advanced disease there is, in addition, hepatosplenomegaly and xanthelasma (PBC is a cause of secondary hypercholesterolaemia). Asymp-tomatic patients may be discovered on routine examination or screening to have hepatomegaly, a raised serum alkaline phosphatase or autoantibodies. Patients with advanced disease may have steatorrhoea and malabsorption of fat-soluble vitamins owing to decreased biliary secretion of bile acids and the resulting low concentrations of bile acids in the small intestine. Auto-immune disorders, e.g. Sjogren's syndrome, scleroderma and rheumatoid arthritis, occur with increased frequency.

Investigations

■ A raised serum alkaline phosphatase is often the only abnormality in liver biochemistry.

■ Serum AMAs are found in more than 95% of patients and a titre of 1 : 160 or greater makes the diagnosis highly likely. M2 antibody is specific. Other non-specific antibodies, e.g. antinuclear factor, may also be present.

■ Serum IgM may be high.

■ Liver biopsy shows loss of bile ducts, lymphocyte infiltration of the portal tracts, granuloma formation in 40% and, at a later stage, fibrosis and eventually cirrhosis.

■ An US scan is sometimes performed in the jaundiced patient to exclude extrahepatic biliary obstruction.

PBC is almost certainly present if the serum alkaline phosphatase and IgM concentrations are both raised and the antimitochondrial antibody test is positive. Liver biopsy provides information about disease stage and prog-nosis, but is not essential to make the diagnosis.

Management

Treatment is with lifelong ursodeoxycholic acid (10-15 mg/kg daily by mouth), a naturally occurring dihydroxy bile acid. It slows disease progression and reduces the need for liver transplantation. The mechanism of benefit is incompletely understood. It should be given early in the asymptomatic phase. Pruritus may be helped by colestyramine, and malabsorption of fat-soluble vitamins (A, D, K) is treated by supplementation. Liver transplantation is indicated for patients with advanced disease (serum bilirubin persistently >100 |imol/L).

Asymptomatic patients may show a near-normal life expectancy. In sympto-matic patients with jaundice there is a steady downhill course, with death in approximately 5 years without transplantation.

Secondary biliary cirrhosis

Cirrhosis can result from prolonged (for months) large duct biliary obstruction. Causes include bile duct strictures, CBD stones and sclerosing cholangitis. US examination followed by MRCP is performed to outline the ducts. ERCP may then be necessary to treat the cause, e.g. stone removal.

Hereditary haemochromatosis

Hereditary haemochromatosis (HH) is an autosomal recessive disorder with a prevalence in the Caucasian population of 1 in 400, with approximately 10% of the population being gene carriers. There is excess iron deposition in various organs, leading to eventual fibrosis and functional organ failure.

Aetiology

HH is characterized by inappropriately increased iron absorption from the upper small intestine. In most cases, HH is due to a mutation in the gene HFE on the short arm of chromosome 6. The normal HFE protein is expressed in the small intestine and plays a role in the regulation of iron absorption. Two missense mutations of the HFE gene account for most patients with HH: a change of cysteine at position 282 for tyrosine (C282Y mutation) or a change of histidine at position 63 to aspartate (H63D mutation). Human leucocyte antigen (HLA)-A3, -B7 and -B14 occur with increased frequency in patients with HH compared with the general population. In a minority of patients, iron overload is due to defects in other proteins involved in iron metabolism.

Clinical features

Most patients are diagnosed when elevated serum iron or ferritin levels are noted on routine biochemistry, or screening is performed because a relative is diagnosed with HH. Presentation may also be with symptoms and signs of iron loading in parenchymal organs (Table 4.11). There is a reduced incidence of overt disease in women because of extra iron losses associated with menstruation and a smaller dietary intake of iron.

Table 4.11 Clinical presentation of haemochromatosis
Health screening (often symptomatic)
Abnormal liver biochemistry
Abnormal iron studies
Familial and/or population screening
Symptomatic disease due to iron deposition in:
• Liver: hepatomegaly, lethargy
• Pancreas: diabetes mellitus
• Myocardium: cardiomegaly, heart failure, conduction disturbances
• Pituitary: loss of libido, impotence
• Joints: arthralgia
• Skin: hyperpigmentation

Investigations

■ Serum liver biochemistry is often normal even with cirrhosis.

■ Serum iron is elevated and total iron-binding capacity (TIBC) reduced. Transferrin saturation (serum iron/TIBC) is >45% (normal <33%).

■ Serum ferritin reflects iron stores and is usually greatly elevated (often >500 μg/L).

■ Genotyping (by PCR reaction using whole blood samples) for mutation analysis of the HFE gene is performed in patients with elevated ferritin and transferrin saturation.

■ Patients with abnormal iron studies and mutations of the HFE gene are treated by phlebotomy without the need for liver biopsy. Assessment of the degree of fibrosis is performed by non-invasive tests (p. 143) or liver biopsy in patients who are predicted to have significant hepatic injury (abnormal liver biochemistry or serum ferritin >1000 μg/L). Liver biopsy and measurement of hepatic iron content is performed if the diagnosis is in doubt.

Causes of secondary iron overload, such as multiple transfusions, must be excluded. In addition, in alcoholic liver disease hepatic iron stores may increase. The precise reason is unknown, but the hepatic iron concentration does not reach the very high levels seen in haemochromatosis.

Management

Excess tissue iron is removed by venesection: 500 mL of blood (containing 250 mg of iron) are removed twice-weekly until iron stores are normalized as assessed by serum ferritin and transferrin saturation. This may need to be continued for up to 2 years and then three or four venesections per year are required lifelong to prevent the reaccumulation of iron. Surveillance (p. 162) for HCC is performed in patients with cirrhosis.

Genotyping to detect HFE mutations and iron studies should be performed on first-degree relatives of affected individuals.

Prognosis

The major complication is the development of HCC in patients with cirrhosis. This can be prevented by venesection before cirrhosis develops, and life expectancy is then much the same as for the normal population.

Wilson’s disease (hepatolenticular degeneration)

This is a rare, recessively inherited disorder. Mutations in the ATP7B gene on chromosome 13 result in decreased secretion of copper into the biliary system and reduced incorporation of copper into procaeruloplasmin, the precursor of caeruloplasmin. Copper accumulates in the liver (leading to fulminant hepatic failure and cirrhosis), basal ganglia of the brain (parkinson-ism and eventual dementia), cornea (greenish-brown rings called Kayser-Fleischer rings) and renal tubules. Diagnosis is made by demonstrating low total serum copper and caeruloplasmin, increased 24-hour urinary copper excretion and increased copper in a liver biopsy specimen. Treatment is with penicillamine or trientene (to chelate copper) or zinc (reduces copper absorp-tion). Liver transplantation is offered to those with end-stage liver disease or fulminant hepatic failure. First-degree relatives are screened and homo-zygotes should be treated.

α1-antitrypsin deficiency

This is a rare cause of cirrhosis. Mutations in the a1-antitrypsin (a1-AT) gene on chromosome 14 lead to reduced hepatic production of a1-AT, which normally inhibits the proteolytic enzyme, neutrophil elastase. The genetic variants of a1-AT are characterized by their electrophoretic mobilities as medium (M), slow (S) or very slow (Z). The normal genotype is PiMM. Most patients with clinical disease are homozygote for Z (PiZZ) and develop chronic liver disease (due to accumulation of the abnormal protein within the liver) and early-onset emphysema due to proteolytic lung damage. Diagnosis is made by demonstrating low serum levels of serum a1-AT and confirmed by genotype assessment. On liver histology, a1-AT-containing globules are seen in hepatocytes. Treatment is for chronic lung and liver disease. Intravenous augmentation therapy with plasma derived a1-AT is used but not widely available. Patients should be advised to stop smoking.

Alcohol and the liver

Alcohol is the most common cause of chronic liver disease in the Western world. Alcoholic liver disease occurs more commonly in men, usually in the fourth and fifth decades, although subjects can present in their 20s with advanced disease. Although alcohol acts as a hepatotoxin, the exact mecha-nism leading to hepatitis and cirrhosis is unknown. As only 10-20% of people who drink excessively develop cirrhosis, genetic predisposition and immuno-logical mechanisms have been proposed.

There are three major pathological lesions and clinical illnesses associated with excessive alcohol intake.

Fatty change

This is the most common biopsy finding in alcoholic individuals. Regular alcohol use, even for a few weeks, can result in fatty liver (steatosis), a disorder in which hepatocytes contain macrovesicular droplets of triglycer-ides. Symptoms are usually absent, and on examination there may be hepatomegaly. Laboratory tests are often normal, although an elevated mean corpuscular volume (MCV) often indicates heavy drinking. The Y-GT level is usually elevated. The fat disappears on cessation of alcohol intake, but with continued drinking there may be progress to fibrosis and cirrhosis.

Alcoholic hepatitis

Alcoholic hepatitis generally occurs after years of heavy drinking and may coexist with cirrhosis. Histologically, in addition to steatosis (see above), there are ballooned (swollen) hepatocytes that often contain amorphous eosi-nophilic material called Mallory bodies, surrounded by neutrophils. There may be fibrosis and foamy degeneration of hepatocytes.

Clinical features

The cardinal sign of alcoholic hepatitis is a rapid onset of jaundice. Other symptoms and signs are nausea, anorexia, right upper quadrant pain, encephalopathy, fever, ascites and tender hepatomegaly.

Investigations

■ Full blood count shows leucocytosis, elevated MCV and often thrombo-cytopenia (resulting from bone marrow hypoplasia and/or hypersplenism associated with portal hypertension).

■ Serum electrolytes are frequently abnormal with hyponatraemia. An elevated serum creatinine is an ominous sign and may predict the devel-opment of hepatorenal syndrome.

■ Liver biochemistry shows elevated AST and ALT with a disproportionate rise in AST (usually AST : ALT ratio >2) and the absolute values for AST and ALT usually <500 IU/L; higher values suggest acute hepatitis due to another cause (p. 148). The bilirubin may be markedly elevated, 300500 |imol/L, reflecting the severity of the illness. Serum albumin is low and prothrombin time prolonged.

■ Microscopy and culture of blood, urine and ascites is performed to search for an underlying infection.

■ US (liver and biliary) is useful to identify biliary obstruction and HCC, which may present similarly.

■ Liver biopsy (often via the transjugular approach because of the abnormal clotting) is not always required. Diagnosis is usually made on the basis of clinical presentation, neutrophilia, elevated INR and liver biochemistry profile.

Management

Patients with severe alcoholic hepatitis require supportive treatment (p. 158) and adequate nutritional intake must be maintained, if necessary via a nasogastric tube. Corticosteroids (40 mg per day for four weeks) reduce the inflammatory process and are indicated if Maddrey's discriminant function >32, indicating severe disease:

[4.6 X (prothrombin time above control in seconds) + bilirubin (mg/dL)]

Bilirubin mmol/L -17 to convert to mg/dL

Steroids are contraindicated if renal failure, infection or bleeding. Pentoxi-fylline, a phosphodiesterase inhibitor with many effects including modulation of TNF-a transcription, also reduces mortality, thought mainly by prevention of hepatorenal syndrome.

Alcoholic cirrhosis

This represents the final stage of liver disease from alcohol abuse. There is destruction of liver architecture and fibrosis, with regenerating nodules pro-ducing micronodular cirrhosis. Patients may be asymptomatic, although they often present with one of the complications of cirrhosis and there are usually signs of chronic liver disease (p. 144). Investigation is as for cirrhosis in general (p. 161). Management is directed at the complications of cirrhosis, and patients are advised to stop drinking for life. Abstinence from alcohol improves the 5-year survival rate.

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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