D-lactic acidosis presenting as metabolic encephalopathy in a patient with short bowel syndrome

Abstract

We present a case of D-lactic acidosis presenting as a metabolic encephalopathy secondary to small intestinal bacterial overgrowth. This patient had a known history of short bowel syndrome. Of note, this case required the alteration of treatment to promote a sustained clinical and biochemical improvement. We discuss the pathophysiological mechanisms thought to be involved. We also review the current therapies as well as potential future strategies. This case highlights the importance of the prompt clinical recognition of signs and symptoms as well as the rapid initiation of management strategies to ameliorate this condition.

Background

D-lactic acidosis is an uncommon form of lactic acidosis, which generally occurs in patients with short bowel syndrome. Short bowel syndrome is a malabsorption condition, which usually occurs following extensive resection of the small intestine. An inability to absorb carbohydrate due to the reduced surface area of the small intestine leads to fermentation by altered colonic bacteria, particularly the Lactobacillus genus.¹ This results in the production of D-lactate, an enantiomer of the more commonly known L-lactate, leading to acidosis.

Case presentation

A 23-year-old man presented to the emergency department with weakness, lethargy and lightheadedness for 1 day. This was on a background of a diagnosis of short bowel syndrome. This resulted following surgical resection of a terminal ileum non-Hodgkin’s lymphoma and subsequent resection of all but 30 cm of small bowel following unexplained infarction of small bowel post primary procedure. Both surgeries occurred when the patient was 5 years old. His ileocaecal valve remained intact. His medical history also included nephrolithiasis and cholelithiasis. Prior to admission he was receiving monthly vitamin B₁₂ injections, alfacalcidol 1 mcg once daily, cholecalciferol 1600 IU once daily, magnesium citrate 300 mg once daily, iron-rich water supplement 5 mg once daily, thiamine 100 mg once daily and an omega fish oil supplement. He had been discharged from hospital 2 weeks prior following an admission for electrolyte disturbance secondary to increased stool frequency. He improved following intravenous fluid and electrolyte replacements. He reported feeling unwell one night prior to presentation at the hospital and his symptoms worsened throughout the day while attending a family event. Bowel frequency of five loose stools per day was noted, but this was unchanged from baseline. He denied any blood or mucous in these stools. He denied any fevers or rigours. Over the preceding weeks, family members reported intermittent episodes of appearing intoxicated despite stringent denials of alcohol consumption or illicit drug use. On initial assessment, he appeared fatigued and was clinically dehydrated. His blood pressure was 128/82 mm Hg and his heart rate was 98 beats/min. The respiratory rate was 19 breaths/min and he maintained an SpO₂ of 100% on room air. He was afebrile. Glasgow Coma Scale was 15/15. Respiratory exam revealed a mild scattered wheeze but cardiovascular examination was unremarkable. His abdomen was soft and non-tender. There was no organomegaly or lymphadenopathy. His bowel sounds were present and normal. No abnormality was found on complete neurological examination. His growth parameters were as follows: weight 66.2 kg, height 1.75 m, body mass index (BMI) 21.6 kg/m².

Investigations

Initial venous blood gases revealed a metabolic acidosis with a pH of 7.11 and bicarbonate of 9 mmol/L. Chloride was 113 mmol/L. There was a high anion gap of 17 mmol/L. The L-lactate reported on this sample was 1.4 mmol/L. A full blood count revealed a leukocytosis (12.5×10⁹/L), which was predominately a neutrophilia (10.7×10⁹/L). His blood glucose was 4.3 mmol/L. C reactive protein was 6 mg/L. Both a chest X-ray and urine dipstick analysis were unremarkable. A hypokalaemia (3.3 mmol/L) was noted. His urea and other electrolytes were as follows: urea 1.2 mmol/L, creatinine 72 μmol/L, sodium 138 mmol/L, adjusted calcium 2.26 mmol/L and magnesium 0.75 mmol/L. No abnormality was detected on liver function tests. An electrocardiograph showed sinus rhythm with a rate of 92 beats/min. CT scan of the brain showed no acute abnormality. A stool culture did not identify typical infective causes for diarrhoea. A D-lactate was requested from an external laboratory.

Differential diagnosis

Many differential diagnoses were considered in this case. Infective causes for increased stool frequency must always be explored early in the presentation. Physicians must also consider other causes for a high anion gap metabolic acidosis such as drug/alcohol intoxication or possibly a starvation ketosis.

However, given this patient’s risk factors and presentation, a presumptive diagnosis of D-lactic acidosis secondary to small intestinal bacterial overgrowth (SIBO) was made.

Treatment

Initial management consisted intravenous fluids to rehydrate the patient given the history of increased stool frequency as well as electrolyte supplementation. Despite this, a metabolic acidosis persisted (pH 7.25, bicarbonate 10.1 mmol/L). Intravenous and oral bicarbonate were then administered.

In addition to this, he was commenced on rifaximin 550 mg twice a day and a low-carbohydrate diet was implemented (maximum 50–100 mg/day).

Outcome and follow-up

Following an acute deterioration involving worsening acidosis and a further episode of encephalopathy, this patient was admitted to the intensive care unit (ICU) for high-dose intravenous bicarbonate infusions. He improved biochemically as well as symptomatically and was discharged from ICU to a medical ward after 2 days. However, after 2 weeks he remained dependant on intravenous bicarbonate infusions which were required to maintain this improvement. As such, rifaximin was switched to a 2-week course of metronidazole. This change, as well as an improved compliance with a low-carbohydrate diet resulted in a recovery of his biochemical as well as clinical status (figure 1). A D-lactate, which was requested from an external laboratory, later returned at >6 mmol/L (normal range: <3 mmol/L), confirming the (presumptive) clinical diagnosis of metabolic encephalopathy secondary to a D-lactic acidosis.

Figure 1.

Flow diagram outlining patient’s progress during admission. ICU, intensive care unit; IV, intravenous.

Discussion

D-lactic acidosis is an uncommon, yet important differential in patients who present with a history of small bowel syndrome. It should be considered in any patient with short bowel syndrome with an unexplained metabolic acidosis or the characteristic neurological sequelae.²

D-lactate is not reported on standard lactic acid assays. As such, in suspected cases a specific request from the laboratory is required early in the presentation. The majority of patients display some form of encephalopathy.¹ Common manifestations include slurring of speech, ataxia and gait disturbance among many others. These symptoms typically present following ingestion of a high-carbohydrate meal.³ A direct toxic effect of D-lactate is not thought to be the cause of the neurologic syndrome.² Infusions of D-lactate to patients without short bowel syndrome do not develop any of the noted symptoms. In addition to this, Cerebrospinal fluid (CSF) concentrations of D-lactate do not correlate with manifestations seen in symptomatic patients. It has been postulated that D-lactate can be toxic in the presence of other metabolites or even vitamin deficiencies that occur in short bowel syndrome.² Further work is needed to determine the pathophysiology of this condition. Management of this condition involves correction of the acidaemia, limiting the intake of carbohydrates and long-term measures including antibiotic therapy or potentially faecal microbiota transplant.⁴

An arterial pH of <7.35 and bicarbonate of <22 mmol/L are characteristic of a metabolic acidosis.⁵ By evaluating the presence or absence of unmeasured anions in the serum, a metabolic acidosis can be defined as a high anion or normal anion gap. Identifying a high anion metabolic acidosis in the context of particular risk factors for D-lactic acidosis on presentation is crucial. In this case, low bicarbonate as well as a raised chloride was identified on the initial venous blood gases. However, it is possible for the serum anion gap to be not elevated in D-lactic acidosis. This is as a result of the efficient excretion of D-lactate anions by two proposed mechanisms. Owing to the inability of D-lactates to bind to the Na⁺/L⁻ lactate cotransporter in the proximal tubule, it is excreted in the urine.⁶ Gastrointestinal (GI) losses of the sodium salt of D-lactate have also been reported.² A concomitant hyperchloraemic metabolic acidosis and high anion gap can occur, as well as a pure hyperchloraemic metabolic acidosis can occur in rare cases. Chronic diarrhoea and GI losses of bicarbonate are the mechanisms leading to the hyperchloraemia in these patients.²

To date, antibiotics remain the mainstay in the management of SIBO.^{7 8} A course of 10 days of treatment is usually sufficient in the majority of patients. However, some patients may require cyclical treatments.⁹ While routine in vitro analysis of antibiotic sensitivities in each unique case would be preferred, this is not a viable option for the majority of institutions. Currently, antibiotic treatment in SIBO is prescribed on an empiric basis. A wide range of antibiotic regimens have been employed and investigated.¹⁰ In recent years, the first line use of rifaximin has been increasingly advocated.¹¹

Rifaximin is a broad-spectrum antibiotic, which has effective cover for both gram-positive, gram-negative as well as aerobic and anaerobic bacteria.¹² Rifaximin is poorly absorbed resulting in a higher bioavailability in the gut and so allows it to be more effective at this site. Its safety and effectiveness has been demonstrated in a large meta-analysis.¹³

Owing to a lack of data, there are no guidelines in the treatment of D-lactic acidosis secondary to SIBO. Currently, the literature consists mainly of case reports in which a variety of antibiotic regimes were used.^14–16 Despite its excellent bioavailability to the GI tract, previous studies have demonstrated persistent lactobacilli growing despite high intraluminal concentrations of rifaximin.¹⁷ This may suggest why metronidazole was found to be much more effective in comparison to rifaximin in this patient.

More recently, researchers have begun to focus on novel management strategies for the treatment of D-lactic acidosis. Successful use of faecal microbiota transplantation has been reported in a child for the treatment of refractory D-lactic acidosis.⁴ Furthermore, a recent case report also suggested a role for the utilisation of probiotic supplementation. This approach resulted in decreased number of D-lactate-producing bacteria in the gut.¹⁸ With the potentially cyclical use of antibiotics to treat this condition, there is a significant risk of developing resistant strains of D-lactate-producing bacteria. Novel approach methods such as microbiota transplantation and probiotic supplementation may obviate the need for antibiotic therapy. Or alternatively may be useful in combination with single antibiotic use for effective treatment.

Dietary manipulation also plays an important role in the management of D-lactic acidosis. Simple carbohydrates are metabolised readily to D-lactate, and so restricting their intake is likely to be beneficial.¹⁹ Favourable results have been reported in patients using such dietary changes, even those requiring multiple courses of antibiotics.²⁰ As in this case, compliance may be an issue. Patient education and counselling is vital to optimise the effect of this intervention.

Learning points.

• D-lactic acidosis should be considered in any patient with short bowel syndrome with an unexplained metabolic acidosis or the characteristic neurological sequelae.

• Rapid initiation of management strategies, such as antibiotics, a low carbohydrate diet and bicarbonate replacement is needed to ameliorate this condition.

• Consider other antibiotic treatments and improving diet compliance if there is a lack of sustained clinical and/or biochemical improvement.