History
A 34-year-old white male was admitted to the hospital after being referred for an ophthalmic consult by his internal medicine team. The patient reported no ocular or visual complaints and had an unremarkable ocular history. 

His medical history was positive for alcohol-induced cirrhosis of the liver. The remainder of his surgical and medical histories were non-contributory. The patient was not currently taking medication and denied any drug allergies.

Diagnostic Data
His best corrected entering visual acuities were 20/20 OD and 20/20 OS at distance and near. 

The pertinent external findings are documented in the photograph. The biomicroscopic examination of the anterior segment was unremarkable and Goldmann applanation tonometry measured 15mm Hg OU. 

The dilated fundus examination was within normal limits with normal cupping measuring 0.2/0.2 and quiet peripheries. 

Your Diagnosis
Does this case require any additional tests? What does this patient’s history and clinical findings tell you about his likely diagnosis? How would you manage this patient? What’s the patient’s likely prognosis? 

This 34-year-old male patient presented with yellowed eyes and skin, but 20/20 vision in both eyes. Can his history aid in his diagnosis?

Discussion
Additional testing included photodocumentation of the presentation for reference and a close inspection of the eyelids to rule out lipid and cholesterol deposition (xanthelasma).

The diagnosis in this issue is scleral icterus secondary to systemic jaundice.^1,2 Scleral icterus is most often the initial presenting sign of jaundice, which in this case was the result of alcohol induced liver cirrhosis. More specifically, jaundice indicates an excess of bilirubin in the bloodstream, typically greater than 2.5mg/dL.²

Red blood cells contain hemoglobin made up of two alpha chains and two beta chains, each containing a heme group.^1,2 At the end of its life cycle, the RBC is taken up by monocytes where the heme group is eliminated, first by being converted to biliverdin and then later to bilirubin.² Bilirubin is not water-soluble and cannot be excreted alone into the blood stream. As such, bilirubin is released from monocytes into the blood as a complex with albumin.³ This complex reaches the liver where it is taken up by hepatocytes.³ The albumin is then removed and bilirubin is conjugated with one or two molecules of glucuronic acid This makes it again water soluble. Only when the bilirubin molecule is bound to glucuronic acid, not albumin, is it considered to be in the conjugated form. This now water-soluble bilirubin is moved into the gallbladder where it is combined with bile. Bile is stored in the gall bladder and released after meals to aid in the breakdown of fatty foods for digestion. Cirrhosis (pathologic hardening of the liver) impairs the processing of bilirubin at the hepatocyte level. Consequently, the body retains bilirubin (conjugated and or unconjugated), which has a yellow hue, in the blood stream and manifests systemically as jaundice, scleral icterus, pruritis, and less often as skin xanthomas when the pigment is seen through the capillaries.^1-3

It is the excess bilirubin, a bile pigment, which gives the yellowing appearance of the eyes, skin, and mucous membranes.^1-4 Though termed “scleral” icterus, it is actually the conjunctiva that contains the bilirubin because of its rich supply of blood vessels. In fact, the sclera contains almost no pigment.⁴ The sign itself is not a diagnosis, instead it suggests several underlying disorders involving liver disease and less frequently blood disorders.^1-4

The main differential diagnoses are divided into two classes based upon the location of the abnormality in the bilirubin processing pathway. Those causes producing an unconjugated hyperbiliruinemia result from abnormalities which occur before bilirubin is bound to glucuronic acid in the hepatocyte.⁴ These diseases include Gilbert’s syndrome (a fluctuation of the enzyme that conjugates bilirubin), hemolytic anemia, or large gastrointestinal bleeds.² These blood disorders produce an excess of damaged RBCs with heme groups that must be metabolized. The number of heme groups that must be processed is greater than what the normal liver can metabolize, resulting in a liver which cannot complete the conjugation process. The result is unconjugated hyperbiliruinemia and jaundice.^1-4

In contrast, conjugated hyperbilirubinemia results from aberrations that occur after bilirubin is conjugated to glucuronic acid. Though it is previously also bound to albumin at the monocyte level, this form is still considered unconjugated. Typically the pathology involves the biliary system. Disease entities in this category include gallstone disease (choledocholithiasis), fibrosis/stricturing of the biliary system which is a sequelae of various systemic ailments or may be a post-surgical complication, and pancreatic disorders such as pancreatitis or pancreatic adenocarcinoma.⁵

Hepatocellular disorders, such as hepatitis (either viral, drug-induced, or alcohol induced), cirrhosis, and hepatic neoplasms (either primary or secondary) can produce both an unconjugated and a conjugated hyperbilirubinemia.³ They do so by either impairing bilirubin uptake into hepatocytes, or impairing hepatocyte processing and excretion.²

There are a few documented cases of unilateral scleral icterus. These cases are unrelated to the aforementioned pathology. In the case of a resolving subconjunctival hemorrhage, the stagnant blood undergoes local metabolism which produces bilirubin at the scene of the injury giving it a yellow color.^6,7 The same process occurs in all bruises accounting for the yellow appearance accompanying resolving “black and blue” marks throughout the body. There have also been three unilateral cases of unilateral scleral icterus following choroidal hemorrhage seen during or just after ocular surgery.¹ The speculated mechanism for this is via interocular movement of yellow subretinal fluid.³

The ophthalmic provider should recognize scleral icterus and understand the possible underlying etiologies to ensure prompt and accurate testing/referral. The condition itself cannot be treated; treatment is of the underlying cause. It is a critical diagnosis to make as it may be the initial manifestation of a manageable life threatening illness.

Dr. Gurwood thanks Bisant Labib, OD for contributing this case. 

1. Roche, SP. Jaundice in the adult patient. American Family Physician. 2004;69(2):299-304.
2. Baudendistal, T. Jaundice. In: Pratt, DS. Harrison’s Principles of Internal Medicine. Philadelphia, PA, McGraw-Hill Companies, Inc. 2012:298-315.
3. Kumar, V. The Liver, Gall Bladder, and Biliary Tract. In: Dimagno, MJ. Basic Pathology. Philadelphia, PA, Saunders. 2007:631-643.
4. Tripathi, RC. Conjunctival icterus not scleral icterus. The Journal of American Medical Association. 1979;242(23):1-3.
5. Tolentino, FI. Unilateral scleral icterus due to choroidal hemorrhage. Archives of Ophthalmology. 1963;70(3):358-360.
6. Aggarwal, P. Scleral icterus may be unilateral. Annals of Emergency Medicine. 1993;22(11):341-350.
7. Ng, BJ. Unilateral icterus and no ‘glass eye.’ Internal Medicine Journal. 2012;115(5):734-736.