Behind The Medical Headlines

The trouble with alcohol… Part 1: Liver disease

• Dr S Al-Shamma, Specialist Registrar, Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK
• Dr MG Lombard, Consultant Physician and Hepatologist, Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK

Summary

In the first of a two-part series on alcohol, Drs Safa Al-Shamma and Martin Lombard from the Royal Liverpool University Hospital discuss the diagnosis and management of alcoholic liver disease.

Declaration of interests: None declared.

Alcohol consumption and liver disease

Alcohol, in its scientific definition, is used to denote any organic compound where a hydroxyl group (OH) is bound to a carbon atom of an alkyl group (C_nH_2n+1). In its more common usage, the term alcohol tends to refer to a large variety of alcoholic beverages, which are widely consumed by the general population. The only alcohol compound suitable for such purposes is ethanol (C₂H₅OH), which is produced when glucose is fermented by yeast. Despite the wide-ranging side effects of alcohol, the liver is the main organ to be damaged by excess alcohol since ethanol is metabolised by the liver. However, the development of liver disease is not a universal finding in patients who consume dangerous amounts of alcohol. As with any complex disease process, alcoholic liver disease (ALD) seems likely to result from the interaction of numerous behavioural, genetic and environmental factors. The amount of alcohol ingested and the pattern of consumption are important predictors of ALD. It is the absolute volume of alcohol, as opposed to the volume of the alcoholic beverage, that is important in ALD. A widely cited epidemiological study by Lelbach et al.¹ estimated that consumption of 80 mg of alcohol per day over a period of 10–20 years will lead to cirrhosis in around 20% of cases. It also estimated that only 50% of drinkers with a daily alcohol consumption of 230 mg (around 30 units or 750 ml of spirits) will develop cirrhosis at 20 years.¹ Therefore, other risk factors must be involved and are likely to have a significant influence. At present, however, they are not fully understood.

Nutritional and genetic factors in predicting liver disease

In recent years, research has focused on identifying individuals most at risk of developing liver disease to improve targeting and treatment. Poor nutrition is often associated with excess alcohol consumption and is thought to worsen ALD. Alcohol excess leads to malnutrition by suppressing appetite and interfering with the intestinal absorption of nutrients. However, malnutrition is not a prerequisite for developing liver disease, which may occur in a well-nourished individual.

Obesity may prove to be as much a risk factor for ALD as malnutrition. It is often difficult to disentangle non-alcoholic from alcoholic fatty liver disease, and effects may be synergistic. Naveau et al.² found a body mass index (BMI) above 25, in combination with excess alcohol consumption for at least ten years, to be an independent risk factor for alcoholic hepatitis and cirrhosis. This is concerning in view of the obesity epidemic in Western society. Other dietary factors, such as coffee consumption, have been shown to have a protective effect against cirrhosis and the development of hepatocellular carcinoma.

Genetic factors can also influence disease risk. Twin studies confirm not only concordance (the presence of the same trait in both twins) for alcohol dependence, but also for cirrhosis, with almost three times higher rates of concordance in monozygotic versus dizygotic twins. In Asians, polymorphisms (variations) of ethanol-metabolising enzymes, such as aldehyde dehydrogenase 2, are associated with an increased incidence of facial flushing after drinking alcohol.

Cytokines, a group of signalling proteins, appear instrumental in perpetuating the liver disease process. Increased reactivity of B-cells and T-cells and increased expression of major histocompatibility complex DR antigens are involved, and elevated levels of endotoxin (lipopolysaccharide) have been detected in the blood of alcoholics. Circulating cytokines, such as tumour necrosis factor-alpha and interleukin-6, have also been associated with the development of ALD. Numerous polymorphisms linked to the cytokine response have been postulated to predispose to ALD, but the data are often conflicting.

Women are more at risk than men. Factors other than the volume of distribution are thought to be involved, for example lower activity of gastric alcohol dehydrogenase, which contributes to alcohol metabolism. High levels of oestrogen are also believed to play a role. Oestrogen increases gut permeability to endotoxin in the rat model, and this might lead to an increase in the TNF-alpha response.³

Recognising patterns of alcoholic liver injury

Presentation of ALD is variable and easily missed as many patients are asymptomatic until a late stage. A high index of suspicion is essential. Symptoms are often non-specific and include abdominal pain, diarrhoea, fatigue, nausea and vomiting. The CAGE (Cutting down consumption, drink-related Anger or Guilt, Early morning drinking) questionnaire is a well-validated and sensitive means of identifying at-risk patients. Tactful, non-judgemental questioning is likeliest to yield results, particularly in older women, who may be embarrassed about excess alcohol consumption.

Liver screen

Even in patients with a clear alcohol history, co-existent causes for liver damage may be present. Co-infection with hepatitis C seems to be more common than expected in those with cirrhosis. Hepatitis B should also be excluded. Other parts of the liver screen should include an autoimmune liver screen, immunoglobulin levels, ferritin, alpha-1 antitrypsin levels, alpha-fetoprotein and caeruloplasmin in those aged under 45 years. It is important to interpret ferritin levels with caution: they may be very elevated in some cases as a direct result of liver injury. Transferrin saturation is a useful additional marker in such cases before performing genetic analysis for haemochromatosis; it is often normal or low.

Fatty liver

There is a spectrum of liver diseases resulting from hazardous alcohol consumption: fatty liver disease, alcoholic hepatitis and cirrhosis. Fatty liver disease occurs possibly as a result of increased synthesis, impaired secretion and the consequent accumulation of triglyceride (the chemical form in which most fat exists in food as well as in the body) in hepatocytes (the chief functional cells of the liver). Fatty liver is most often asymptomatic. A rise in gamma glutamyl transpeptidase (GGT) and (mild) transaminase elevation are possible findings. Ultrasound examination sometimes reveals a diffuse bright liver echo pattern, although a liver biopsy is the only way of making a definitive diagnosis. This is generally unnecessary as most cases are reversible on cessation of alcohol consumption.

Alcoholic hepatitis

Alcoholic hepatitis is a form of liver injury that can range from asymptomatic to severe life-threatening disease. It occurs in up to 35% of those who drink at dangerous levels and is often associated with malnutrition. Severe hepatic decompensation may occur, leading to gastrointestinal bleeding, coagulopathy, encephalopathy and death. Although aspartate aminotransferase (AST) rarely exceeds 300, a transaminase may be elevated, in addition to severe hyperbilirubinaemia (above 500 µmol/L) in some instances. This is a reflection of underlying disease severity. Leucocytosis, an elevation of the white blood cell count, is a commonly found feature.

Treatment is largely supportive, but clinical algorithms and scores (e.g. the Maddrey discriminant function or Glasgow alcoholic hepatitis score) can have a role in predicting those patients likely to benefit from steroids. If steroids are used, sepsis needs to be excluded (a diagnostic ascitic tap is essential in all those with ascites). The evidence for steroid use is controversial. Pentoxifyllin, a phosphodiesterase inhibitor with weak anti-TNF-alpha activity, has been shown in small case series to improve prognosis.⁴ Despite the inconclusive evidence, a trial of either steroids or pentoxifyllin is sometimes worthwhile in those with severe alcoholic hepatitis since mortality can be as high as 50%. The development of renal failure is an ominous sign with a grave prognosis. Prevention, by avoiding sepsis and careful fluid balance, is vital. Dialysis does not alter outcome.

Cirrhosis and complications

Alcoholic cirrhosis is the end stage of liver damage and represents irreversible liver injury. Cirrhosis can be asymptomatic with no clinical signs and normal blood investigations (compensated cirrhosis). Alternatively, patients may present with severely decompensated disease with gross ascites, encephalopathy and coagulopathy. Aspartate transaminase (AST) or alanine transaminase (ALT) may be normal or elevated but again rarely exceeds 300, with an AST/ALT ratio above 2. Hypersplenism may occur, leading to thrombocytopaenia and leucopaenia – both may be profound. A coarse, nodular liver is a characteristic finding on ultrasound or computed tomography, although imaging may be normal. All patients should undergo an endoscopy to screen for varices and, if found, B-blockade therapy should be instituted unless contra-indicated. A banding programme should only be undertaken if there has been a previous variceal bleed or if the patient is intolerant to B-blockers.

The use of normal saline should be avoided. As with alcoholic hepatitis, the development of renal failure or hepatorenal syndrome (HRS) is a dreaded complication. Judicious fluid replacement is required as over-vigorous resuscitation may worsen ascites and precipitate hyponatraemia. The use of 20% albumin and intravenous terlipressin appears to confer some benefit in HRS. As with alcoholic hepatitis, dialysis is not often useful.

Clinical management

The role of aggressive nutrition (via a nasogastric feeding tube if necessary) should not be underestimated as it is associated with a definite reduction in mortality.⁵ Long-term nutritional supplements also improve the outcome in cirrhotics, due to a reduced risk of severe infections.⁶ Vaccination against hepatitis A and B is an important yet often forgotten protective strategy. Other general measures include B-complex vitamin supplementation and thiamine (particularly before dextrose infusion), lactulose to reduce the risk of encephalopathy and a low salt diet for those with ascites. There is no role for a low protein diet. A one-off dose of 10 mg vitamin K intravenously is used to correct coagulopathy, but is often unsuccessful as deficiency is rarely the sole cause. The use of fresh frozen plasma is not indicated unless there is evidence of active bleeding.

Ascites

Ascites is an accumulation of fluid in the peritoneal cavity, due to sodium and water retention, with consequent changes in the splanchnic microcirculation. Spironolactone, a specific aldosterone antagonist, and low-dose furosemide, a natriuretic loop diuretic, are the mainstays of treatment, along with salt restriction. Daily weight measurement is the simplest means of assessing response, yet is often neglected.

Massive ascites is difficult to manage, and large-volume paracentesis (above 5 litres) should be undertaken if no response to increasing diuretics is achieved. Paracentesis, a procedure in which a needle or catheter is inserted into the peritoneal cavity to obtain ascitic fluid, reduces complications related to high-dose diuretics, such as hyponatraemia and renal failure. The benefits of paracentesis also include a reduced risk of variceal haemorrhage, due to a reduction in the hepatic venous pressure gradient. To avoid complications associated with fluid shifts secondary to large-volume paracentesis (mainly hypotension and acute renal failure), protein is replaced at 8 g per litre of ascites removed (approximates to 100 ml of 20% albumen per 3 l).

Resistant ascites requiring regular paracentesis is a poor prognostic sign and an indicator of underlying severe hepatic and renal dysfunction. A transjugular intra-hepatic porto-systemic shunt (TIPSS) is occasionally required in such cases if the patient is considered unsuitable for liver transplantation. A patent portal vein is a prerequisite for such a procedure.

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis is a grave complication presenting with decompensation of liver disease, abdominal pain and fever (or occasionally asymptomatic) and requiring urgent antibiotic therapy with third-generation cephalosporin or quinolones. Ascitic fluid analysis and cultures (into standard blood culture bottles) should be obtained. Infusions of 20% human albumin on days one and three after diagnosis have been shown to improve prognosis.⁷ Life-long prophylactic antibiotics with oral quinolones should be prescribed afterwards as recurrence is common.

Variceal haemorrhage

Oesophageal variceal haemorrhage is a potentially life-threatening event, requiring urgent aggressive resuscitation, intravenous terlipressin (or other vasopressor agent), antibiotic prophylaxis, the correction of clotting and urgent endoscopy - once the patient has been stabilised. Endoscopic variceal banding should be undertaken on several occasions after the event in order to obliterate varices. Patients with gastric varices are more difficult to manage and require specialist care. A TIPSS procedure may be required to decompress varices in cases of uncontrollable haemorrhage.

Encephalopathy

Encephalopathy, damage to the brain and nervous system that occurs as a complication of liver disorders, may be difficult to manage and has a limited evidence base for treatment. The exclusion and correction of any precipitant factors such as electrolyte disturbance, constipation, hypoxia, haemorrhage or sepsis are essential. Patients may range from being slightly confused to deeply comatose. A hepatic flap is a usual but non-essential feature. Ammonia levels can be elevated, but generally have no place in diagnosis. Lactulose or phosphate enemas may be required to ‘cleanse’ the bowel.⁸ Neomycin can be used in the short term in more resistant cases.

Prognosis and liver transplantation

Abstinence remains the single most important factor in determining prognosis in alcoholic cirrhosis. The Child-Pugh classification includes five variables: albumin, ascites, bilirubin, encephalopathy and prothrombin time. One-year survival in ‘Child A’ patients approaches 100%, while it can be as low as 40% in ‘Child C’ patients.⁹. Overall, if a patient can remain abstinent, the five-year survival is around 60–70%. In those who continue to drink, it is as low as 40%. An improvement of fibrosis as well as a reduction in portal pressure have been noted in some patients who completely abstain. However, the disease process may continue to progress despite strict abstinence. Aminotransferases may remain elevated for many months and should not be relied upon as accurate indicators of abstinence.

The life-time risk of hepatocellular carcinoma in cirrhosis is difficult to assess accurately. It is thought to be greater than 10%. Annual follow-up with ultrasound examination of the liver and alpha-fetoprotein measurement is the recommended practice, although without a strong evidence base.

Liver transplantation is an option for those who can demonstrate abstinence. No absolute interval is required, but six months of sobriety are often sought. The prognosis is excellent and comparable to other transplant patients if abstinence can be maintained. A thorough psychological evaluation is undertaken to ensure the likelihood of abstinence as well as future compliance. However, in suitable candidates liver transplantation should be considered and offered without any bias.

Patient resources

British Liver Trust

Patient UK on alcohol and liver disease

Alcoholics Anonymous

References

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2. Naveau S, Giraud V, Borotto E et al. Excess weight risk factor for alcoholic liver disease. Hepatology 1997; 25(1):108–11.
3. Enomoto N, Yamashina S, Schemmer P et al. Estriol sensitizes rat Kupffer cells via gut-derived endotoxin. Am J Physiol Gastrointest Liver Physiol 1999; 277:G671–7.
4. Akriviadis E, Botla R, Briggs W et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000; 119(6):1637–48.
5. Marchesini G, Dioguardi FS, Bianchi GP et al. Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. J Hepatol 1990;11(1):92–101.
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7. Sort P, Navasa M, Arroyo V et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341(6):403–9.
8. Als-Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev 2004;(2):CD003044.
9. Infante-Rivard C, Esnaola S, Villeneuve JP. Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics. Hepatology 1987; 7(4):660–4.