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Diseases of the Liver 6 and Gastrointestinal Tract

L. Roy Eversole, DDS, MSD, MA


Hepatobiliary diseases, 54 Pathophysiology, 55 Clinical features, 56 Dental management, 56 Gastrointestinal diseases, 57 Pathophysiology, 57 Clinical features and oral manifestations, 58 Suggested reading, 60

Hepatobiliary diseases
Liver diseases include infections, particularly with viruses, cirrhosis, drug-induced lesions, and neoplasms. Viral hepatitis is discussed in detail in Chapter 16 and is not covered in this chapter. Cirrhosis is the result of progressive degenerative changes in the liver whereby hepatocytes undergo necrosis and are replaced by fibrous scar. The primary causes of cirrhosis include post-viral fibrosis, alcohol abuse, and biliary obstruction. The clinical consequences of cirrhosis are, of course, related to loss of hepatocyte function. Liver cells are the source of many proteins, including albumin, and five factors essential for coagulation; therefore, edema and a hemorrhagic diathesis occur in cirrhotic patients. Estrogen metabolism is impaired and drug clearance is decreased. Scarring in the liver also results in vascular stasis and portal hypertension, which presents clinically with angiectasias of the esophagus, rectum, and periumbilicus. Biliary disease is usually attributed to bile duct stasis resulting from accumulation of stones (cholelithiasis), although, importantly, obstructive disease can result from tumor compression of the common bile duct (eg, pancreatic carcinoma). Conjugated (direct) bilirubin is typically elevated, as is the liver-specific alkaline phosphatase isoenzyme. In severe prolonged biliary obstruction, cirrhosis develops and results in the same clinical complications of liver failure that occur in alcoholic or post-viral cirrhosis. Cancer of the liver is more often metastatic than primary. Colon carcinomas metastasize via the portal vein, and cancer cells deposit in the liver via this portal circulation. Hepatocellular carcinoma, or primary liver cancer, is strongly related to infection with hepatitis B, a
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virus that can trigger oncologic events in hepatocytes. Late-stage liver cancer, either primary or metastatic, culminates in jaundice, bleeding tendency, and eventual emaciation.
Central vein

Hepatocytes

Glucuronyl transferase Bilirubin (unconjugated) Bilirubin diglucuronide (conjugated)

RBC hemolysis

Portal vein

Bile duct

Figure 61 Unconjugated bilirubin is derived from red blood cell (RBC) lysis and is transported from the portal vein into the sinusoids where it enters hepatocytes and is glycosylated to become conjugated bilirubin. The conjugated form leaves by way of the bile canaliculi and drains into the bile duct.

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Pathophysiology Erythrocytes are normally lysed after 120-day life spans. The hemoglobin is catabolized to heme, iron, and peptides (Figure 61). The heme ring is first converted to biliverdin and bilirubin, which is then transported across the hepatocyte membrane for eventual elimination. Bilirubin enters the hepatocyte from the portal circulation as an unconjugated (indirect) form that is conjugated within the hepatocyte cytoplasm to glucose by an enzymatic process to form bilirubin diglucuronide (direct bilirubin). This conjugated form is transported out of the hepatocyte, into the cholangioles and is then collected in the gall bladder. During the digestive process, bilirubin leaves the bladder along with bile salts to enter the stool where it is converted to stercobilin and then to urobilinogen. Excess amounts of urobilinogen can be reabsorbed into the mesenteric vessels and through the circulation, into the urine. Jaundice or icterus occurs when bilirubin is retained in the blood stream (Figure 62). Elevated serum levels of bilirubin are the consequence of increased hemolysis, hepatocyte damage, and destruction to the outflow of bile through the biliary tree. In hemolytic anemias, excessive hemolysis results in release of high levels of unconjugated bilirubin, more than the liver can assimilate, and the result is a typical unconjugated (indirect) hyperbilirubinemia. Increased amounts of conjugated bilirubin flow into the biliary tract, enter the circulation, and ultimately are lost in the urine, accounting for elevated levels of urine urobilinogen. When hepatocytes drop out because of infection or toxins, unconjugated bilirubin begins to accumulate. In the remaining functional hepatocytes, bilirubin is conjugated and begins to accumulate in the serum. Thus, in hepatitis and cirrhosis both unconjugated (indirect) and conjugated (direct) hyperbilirubinemia develop. Because bilirubin enters the bile ducts in low quantity, urobilinogen formation is decreased so that urine urobilinogen levels are low. Unlike unconjugated bilirubin, the conjugated form can be filtered through the kidneys with resultant bile in the urine (choluria). Similar findings may be seen in genetic liver diseases, such as rotor, Dubin-Johnson, Crigler-Najjar, and Gilbert syndromes, in which transport and conjugating enzyme proteins are mutated. Primary biliary cirrhosis is intrahepatic and involves autoimmune mechanisms that lead to inflammatory lesions around bile canaliculi and portal triads. Elevated antimitochondrial antibody titers are observed. Biliary atresia is a congenital defect in which the bile duct system fails to form, thereby leading to severe biliary cirrhosis in children. Secondary or extrahepatic cholestasis is the result of cholangitis, cholelithiasis, and compression from tumors and from strictures of the bile duct. In biliary cirrhosis hepatocytes are capable of bilirubin

uptake, conjugation and release such that conjugated bilirubin enters the cholangioles. Owing to stasis resulting from biliary occlusion by stones or tumors, conjugated hyperbilirubinemia occurs with concurrent choluria and absent urinary urobilinogen. Because bile salts are also retained as a consequence of bile obstruction, they cannot reach the small intestine. Intestinal lipids are not emulsified, leading to malabsorption of fat-soluble vitamins and steatorrhea. Avitaminosis K promotes coagulopathy, whereas avitaminosis D can result in osteodystrophy. Common to all diseases with hepatocyte damage and dropout is coagulopathy, because the liver synthesizes five clotting factors. Prothrombin and partial thromboplastin times are prolonged, and the international normalized ratio (INR) is increased. Certain enzymes are intrinsic to hepatocytes (aminotransferases), and when hepatocytes undergo necrosis, these enzymes become extracellular, and they are absorbed into the liver sinusoids to become elevated in serum. Liver-specific alkaline phosphatase isoenzymes derived from cholangioles become elevated in biliary obstruction. Primary hepatocellular carcinoma is a malignant tumor of hepatocytes. There is a well-documented marked increased risk for this cancer among persons previously infected with hepatitis B virus. The tumor can remain silent for months or even years. It is not until liver function becomes compromised that symptoms surface. The molecular basis for oncogenesis by the virus is not well-known. Hepatitis B encodes HBx, a

UCB CB

Conjugation

UCB Urinary bladder CB UBL CB

Gall bladder

UBL Figure 62 In hemolytic anemias, unconjugated bilirubin (UCB) is elevated in the serum and increased levels of conjugated bilirubin (CB) are converted to urobilinogen (UBL), which is reabsorbed from the gut and eliminated in the urine, causing increased levels. In hepatocyte destruction, both UCB and CB are elevated. In biliary obstruction, UCB is elevated in the serum and accumulates in urine (choluria).

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protein that transactivates cellular oncogenes and upregulates protein kinase C, an important enzyme involved in signal transduction.

Clinical features There are signs, symptoms, and complications of liver failure that are common to all forms of hepatonecrosis and cirrhosis, and there are yet other features that are unique to each of the disease processes previously discussed. Common to all forms of liver-cell destruction and failure are jaundice, edema, and a hemorrhagic diathesis. In alcoholic cirrhosis, patients often exhibit vascular dilatations affecting vessels that anastomose with the portal vein. Esophageal, umbilical, and hemorrhoidal veins become distended or varicose as a consequence of portal hypertension. Esophageal varices can be particularly problematic, since they may rupture and lead to uncontrolled internal hemorrhage. The facial skin is prone to show multiple telangiectasias in alcoholic cirrhosis. Hepatocyte damage results in low-level synthesis of albumin, a liver-engendered protein important in the maintenance of osmotic balance. Hypoalbuminemia lowers blood osmotic pressure with resultant exit of fluid from the vascular compartment to the interstitial fluid compartment (edema). Gynecomastia in males is the consequence of diminished catabolism of estrogenic hormones, an enzymatic pathway found in the hepatocyte. In post-hepatitis cirrhosis, patients may have generalized malaise and low-grade relapsing fevers, depending upon how active or inactive the infection may be. During active infection, hepatomegaly is observed; in cirrhosis, the liver is no longer palpable, owing to scarified shrinkage. In alcoholic cirrhosis, the patient may manifest other signs and symptoms of alcoholism that are readily observable (intoxication behaviors). Patients with biliary cirrhosis may complain of epigastric or infrasternal pain and cramping attributable to gallstones, tumor, or other forms of bile duct stricture. A common symptom in biliary cirrhosis is generalized pruritus. Other findings indicative of biliary obstruction

are palmar erythema, particular of the thenar and hypothenar eminences, cutaneous xanthomas secondary to elevated low-density lipoproteins that accompany biliary disease and clubbing of the nails. Children with biliary atresia present with green teeth, owing to the dentinal incorporation of bilirubin pigment. The diagnosis is made by history, serology for viral antigens and antibodies, laboratory assessment of serum chemistries, and liver needle biopsy. Table 61 outlines the salient laboratory findings in the various forms of liver disease. Patients with end-stage liver disease are candidates for transplantation. Like other organ transplant recipients, patients receiving liver transplants must undergo transplantation antigen testing and tissue cross-matching. Exact tissue matches, except between identical twins, are not feasible, and therefore, recipients are placed on immunosuppressive medications, typically cyclosporine and prednisone.

Dental management The primary dental management concerns for patients with hepatobiliary disease are infection control for hepatitis viruses, drug metabolism, and importantly, potential coagulopathy. Infection-control issues are of paramount importance, because hepatitis B virus is highly resistant to many disinfectants. Both hepatitis B and C are transmissible from actively infected patients and carriers in the dental office environment. The hepatitides are discussed in detail in Chapter 16, and methods for managing patients with transmissible diseases are discussed in detail in the Chapter 19. Many drugs are catabolized in the liver by the cytochrome P-450 pathway. In hepatitis and cirrhosis, hepatocyte damage and nonfunction lead to prolonged and cumulative drug activity. This is an important consideration for patients requiring analgesics and sedatives. Pain drugs with codeine, oxycodone, and hydrocodone remain active longer, and either dosage or periodicity of intake should be altered appropriately.

Table 61

Blood Chemistries in Jaundice and Liver Disease Bilirubin UC C/UC C/UC C Absent Urobilinogen +++ + + Absent Absent Choluria Absent + + +++ Absent Hepatitis Serology Negative Negative Positive Negative Positive

Disease Group Hemolytic anemia Alcoholic cirrhosis Postinfectious cirrhosis Biliary cirrhosis Hepatocellular carcinoma*

*Carcinoma in the late course may show elevations in bilirubin. UC = unconjugated or indirect bilirubin; C = conjugated or direct bilirubin.

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Antibiotics also are retained longer in circulation; however, this may be a benefit rather than a concern. Perhaps the most significant aspect of hepatobiliary disease to consider in the dental patient is coagulopathy. In active acute hepatitis, failure to synthesize prothrombin as well as other clotting factors can result in extreme hemorrhage during tooth extraction. In chronic hepatitis and all forms of cirrhosis, prolonged bleeding after periodontal surgery and oral and maxillofacial surgery is commensurate with the degree of hepatocyte destruction and can be assessed by ordering a prothombin time (PT) and INR or partial thromboplastin time (PTT). Recall that any patient with less than 50% of normal coagulability is not a candidate for surgical procedures unless special measures are followed. An INR over 3.0 in a cirrhotic patient is also a cause for modification of dental treatments in which hemorrhage will occur. In patients needing immediate care owing to an acute oral infection for which periodontal surgery or extraction is necessary, the patients physician should be consulted, and the patient may have to be hospitalized with intravenous infusion of coagulation-factor replacements. Among patients with only slightly elevated INR or PTs exceeding 50% of normal, added precautions for prolonged bleeding must still be taken. Compression with gauze over wounds should be administered for longer than usual. For postoperative pain, drugs that inhibit platelet adhesion, such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) only compound the bleeding tendency and should be avoided. Prescription of acetometaphine compounded with codeine, oxycodone, or hydrocodone can be prescribed for pain with the caveat that hepatic catabolism of these drugs is impaired. The pre- and post-transplant patient poses a risk, owing to the immunosuppression that is induced during and after the transplant. Dental sepsis should be eliminated in the pretransplant subject, extracting teeth with severe periodontitis and periapical foci of infection. Post-transplant patients taking cyclosporine should be informed about the possibility of developing gingival enlargement. When hyperplasia does evolve, gingivectomy can be undertaken. Oral candidiasis may be a complication of transplantation with immunosuppression and can be treated by prescribing the appropriate antifungal medication (see Chapter 18). Medical management of the patient in liver failure is aimed at preventing life-threatening bleeds, control of edema, and therapy for portal hypertension. Wholeblood transfusions may be administered, and intravenous vasopressor drugs, such as vasopressin, are administered to induce splanchnic constriction. Propranolol has been employed to lessen the degree of esophageal bleeding from varices. In some patients, vascular shunts may be used to lower portal hypertension. Ascites is managed by lowering salt intake and induc-

tion of controlled diuresis with aldosterone blockade. Spironolactone, hydrochlorothiazide, and furosemide may be used to diurese the patient. Weight loss from edema fluids is maintained below 0.5 kg per day, to prevent hypovolemia. In patients with severe hypoproteinemia, infusion of low-salt albumin can be administered to raise the blood osmotic pressure. In patients with extrahepatic biliary disease, cholecystectomy is the treatment of choice when the disease is chronic and imaging studies reveal the presence of large stones. Smaller stones have been treated with chenodeoxycholic acid or its analogue ursodeoxycholic acid; however, cholesterol stones are resistant to dissolution with these drugs. Small stones may also be lysed with lithotripsy, an ultrasonic device that breaks down the mineralized deposits in situ.

Gastrointestinal diseases
Gastric and duodenal ulcer, atrophic gastritis, gluten enteropathy, chronic inflammatory bowel disease, and intestinal polyposis all have dental implications. Upper gastrointestinal (GI) tract ulcers are considered to be a psychosomatic illness, owing to their association with emotional stress. Hematemesis is a sign of severe gastric ulcer disease. When intestinal ulcers remain untreated, they may progress to perforation with resultant peritonitis. Atrophic gastritis is associated with pernicious anemia, a disease that shows characteristic dorsal tongue changes. Patients with atrophic gastritis are at risk for stomach cancer. Gluten enteropathy and the two major forms of chronic inflammatory bowel disease (ulcerative colitis and regional enteritis) all have oral manifestations. Indeed, it is the detection of the oral lesions that may herald the presence of gastrointestinal disease. Polyps are common proliferative lesions of the bowel. Some are hereditary, others are not. Certain polyps are prone to malignant transformation. Both hamartomatous polyps and premalignant adenomatous polyps may be associated with oral and jaw lesions. Colorectal cancer can erode the serosal lining of the gut and lead to internal hemorrhaging that may predispose to anemia, leukopenia, and thrombocytopenia. For the most part, bowel diseases do not directly impact dental treatment. Their significance is primarily linked to the oral and jaw manifestations that are an accompaniment.

Pathophysiology The stomach is lined by a specialized mucous membrane that secretes hydrochloric acid (HCI) while maintaining

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a protective mucinous coating that prevents dissolution of its self. The hormone gastrin that is expressed and secreted during active digestion, mediates the secretion of HCl by gastric epithelium. Autoantibodies and autoreactive T cells can exert immunopathologic damage to the mucosal lining, leading to epithelial atrophy. The atrophic lining is no longer capable of acid secretion (achlorhydria), and elaboration of the intrinsic factor required for vitamin B12 absorption is significantly diminished. Vitamin B12 is a coenzyme required for erythroblastic differentiation and maturation. When vitamin B12 is not absorbed, the maturing erythroblasts are enlarged, hence the term megaloblastic anemia. Mature erythrocytes are also enlarged and engorged with excessive amounts of hemoglobin (macrocytic, hyperchromic), yet the total number of erythrocytes is significantly decreased. Oxygen-carrying capacity is low, with patients showing pallor and exhibiting lethargy. Gastric ulcers occur anywhere in the stomach, although certain regions are more prone. The ulcer is characterized by loss of gastric epithelium. The submucosa is inflamed, and in more severe cases, the inflammatory lesion erodes through the muscularis into the serosa and, in some cases, goes on to ulcerate. Hyperacidity is considered to play a role, yet the presence of Helicobacter pylori is also a major factor in the pathogenesis of this disease. Inflammatory diseases of the small and large intestines are common disorders that appear to involve immunopathologic mechanisms without any known microbial pathogen being isolated from lesional tissue. Gluten enteropathy, also known as celiac disease or nontropical sprue, involves the small bowel and is the result of a hypersensitivity reaction to the wheat gluten allergen, gliadin. IgA antigliadin and antiendomysial antibodies are generally present. Antigen-antibody complexes adhere to the epithelial lining of the gut inducing inflammation with secondary malabsorption of fats (steatorrhea). There is also a defective absorption of fatsoluble vitamins, yet rarely is there significant clinical evidence of osteodystrophy (low vitamin D) or hypoprothrombinemia (low vitamin K). Affected patients suffer from diarrhea and intestinal cramping. Chronic inflammatory bowel disease consists of two common afflictions: ulcerative colitis and regional enteritis or Crohns disease. Ulcerative colitis is characterized by irritable bowel symptoms consisting of watery diarrhea with intervening episodes of constipation. Abdominal cramping is also a feature. The etiology is unknown although emotional stress and tension are predisposing factors. Autoantibodies to colonic mucins and a cytotoxic T-cell response to colonic epithelium have been documented and may play a role in the pathogenesis. There are broad areas throughout the colon that develop linear serpentine ulcerative

streaks. The colonic epithelium is lost, and the lining is replaced by granulation tissue and microabscesses that form in the epithelial crypts. Most of the ulcers are located in the descending colon. Regional enteritis is also characterized by irritable bowel symptoms: constipation alternating with episodes of diarrhea and abdominal discomfort. Inflammatory foci are segmentally distributed within the submucosa and are preferentially localized to the ileum yet may extend into the ascending colon. These inflammatory foci are comprised of nonspecific mononuclear inflammatory cell infiltrates that may occasionally include specific granulomatous inflammation with multinucleated giant cells. The inflammatory segments constrict the bowel and obstruction can become a complication. Lower GI contrast imaging discloses the segmental pattern of disease. Polyps are common nodular lesions of the colon that may occasionally arise in the small bowel. They may be single or multiple, sporadic, or hereditary. Microscopically, intestinal polyps are subdivided into two major categories: benign hamartomatous polyps and adenomatous polyps. The hamartomatous polyps are typically round or oval with a pedunculated stalk. The Peutz-Jeghers syndrome is a heritable condition in which patients develop multiple intestinal hamartomatous polyposis. Importantly, these types of polyps are not precancerous. Colon cancer has been reported to occur in patients with the Peutz-Jeghers syndrome and such cancers are believed to arise from adenomatous polyps that can sometimes be seen in these patients. Adenomatous polyposis coli (APC) is a heritable disease characterized by multiple colonic adenomatous polyps. These polyps are multiple and tend to arise in the transverse and descending colon. The APC gene that encodes a tumor-suppressor protein is mutated in adenomatous polyposis coli, and when both alleles are affected, the polyps transform into adenocarcinomas.

Clinical features and oral manifestations In pernicious anemia associated with atrophic gastritis, patients often manifest tongue changes. The filiform papillae are denuded and often even the fungiform papillae are lost, giving the dorsum of the tongue a beefy red, bald appearance (Figure 63). These same changes may be observed in erythematous candidiasis, which is included in the differential diagnosis (see Chapter 18). A complete blood count, including erythrocyte count, hemoglobin, and hematocrit, discloses a macrocytic hyperchromic anemia. Blood vitamin B12 levels are decreased and gastric analysis discloses achlorhydria. Oral ulcerations resembling aphthae are encountered in patients with gluten enteropathy. These ulcers are oval and small, being less than 5 mm in diameter, and are

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Figure 63 Bald, depapillated tongue in pernicious anemia secondary to atrophic gastritis.

multiple (Figure 64). Unlike aphthae they are persistant and chronic. Any patient with a history of chronic oral ulcerations and intestinal cramping should be evaluated for gluten enteropathy. Screening for serum IgA antiendomysial antibodies is recommended. Antigliadin antibodies can be seen in patients who have negative duodenal biopsies and therefore provide no significant diagnostic information. Skin lesions that are red and papular may also occur in gluten enteropathy. Biopsy discloses eosinophilic infiltrates and deposition of IgA in the dermal papillae, diagnostic features for dermatitis herpetiformis. When the patient is started on a glutenfree diet, the signs and symptoms resolve. Both forms of chronic inflammatory bowel disease show oral manifestations. Some patients with ulcerative colitis develop diffuse serpentine oral erosions that are exudative and erythematous (Figure 65). Biopsy disB

C Figure 65 Pyostomatitis vegetans. A, Clinically, the mucosa shows red and exudative erosions; B, microscopically, intraepithelial eosinophilic abscesses are evident; and C, immunoreactants (IgG) exhibit a pericellular fishnet pattern.

Figure 64

Aphthous-like ulcers in celiac disease.

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Figure 66

Osteomas in the Gardner syndrome.

closes intraepithelial eosinophilic abscesses and immunofluorescence staining often shows a pericellular pattern with anti-IgG, -IgM, or -IgA, a pattern identical to that seen in pemphigus vulgaris (see Chapter 21). This condition is termed pyostomatitis vegetans, and lesions with a similar histologic appearance may arise on the skin where they are called pyodermatitis vegetans. In Crohns disease, patients may have lesions throughout the GI tract, including the small bowel, stomach, and oral cavity. The oral lesions are usually tumefactive and multinodular yet can be erythematous and erosive (see Chapter 24). Histologically, the oral lesions of Crohns disease are similar to those in the bowel, being represented by noncaseating granulomatous inflammation (see Chaper 24). Perioral macular pigmentations are encountered in the Peutz-Jeghers syndrome. The lesions are brown to black and appear as numerous freckles (see Chapter 22). Similar melanotic spots may be observed on the hands and fingers. These patients usually indicate that they have had long-term bowel symptoms that include cramping and diarrhea. The oral and jaw manifestations of the Gardner syndrome are important entities to recognize because they herald the presence of adenomatous polyps. These polyps transform to carcinomas in all patients affected with the syndrome, and once they are detected, colon resection is performed. The jaw manifestations include multiple supernumerary teeth and multifocal radiopaque masses that have been termed osteomas. These bony lesions are readily visualized on dental radiographs where they may be seen overlying the periostium of the jaws or facial bones and within the sinuses (Figure 66). They can often be seen clinically and are indurated.

As mentioned previously, patients with GI diseases do not present a problem for routine dental care. Recognition of the oral manifestations is important, since these manifestations may be the first indication that GI disease is extant.

Suggested reading
Douglas LR, Douglass JB, Sieck JO, Smith PJ. Oral management of the patient with end-stage liver disease and the liver transplant patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:5564. Jokinen J, Peters U, Maki M, et al. Celiac sprue in patients with chronic oral mucosal symptoms. J Clin Gastroenterol 1998;26:236. Seow WK, Shepherd RW, Ong TH. Oral changes associated with end-stage liver disease and liver transplantation: implications for dental management. ASDC J Dent Child 1991;58:47480. Takeuchi T, Takenoshita Y, Kubo K, Iida M. Natural course of jaw lesions in patients with familial adenomatosis coli (Gardners syndrome). Int J Oral Maxillofac Surg 1993; 22:22630. Thomson PJ, Langton SG. Persistent haemorrhage following dental extractions in patients with liver disease: two cautionary tales. Br Dent J 1996;180:1414. Thornhill MH, Zakrzewska JM, Gilkes JJ. Pyostomatitis vegetans: report of three cases and review of the literature. J Oral Pathol Med 1992;21:12833. Wakefield CW, Throndson RR, Brock T. Liver transplantation: dentistry is an essential part of the team. J Tenn Dent Assoc 1995;75:916.

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